Perioperative Ketamine in Opioid-Tolerant Patients Undergoing Lumbar Spine Surgery: A Randomized, Double-blind, Placebo-controlled Trial
Phase: PHASE2
Conditions: Opioid Dependence, Chronic Pain
Sponsor: Jacques E. Chelly

STUDY: Perioperative Ketamine in Opioid-Tolerant Patients Undergoing Lumbar Spine Surgery: A 
Randomized, Double-blind, Place-controlled Trial 
Principal Investigator: Jacques E. Chelly, MD, PhD, MBA 
IRB: STUDY19020144 
NCT: 04220489 
Study Protocol – Approved 09/03/2019 
 

Basic Information 
 
1. * Title of study: 
Perioperative Ketamine in Opioid-Tolerant Patients Undergoing Lumbar 
Spine Surgery: A Randomized, double-blind, placebo-controlled trial 
2. * Short title: 
Perioperative Ketamine in Opioid-Tolerant Patients Undergoing Lumbar 
Spine Surgery 
3. * Brief description: 
The goal of this study is to determine whether comprehensive 
perioperative administration of the NMDA receptor antagonist ketamine can 
increase postoperative pain tolerance and reduce opiate consumption in 
chronic back pain patients undergoing spinal laminectomy/fusion when 
compared to placebo 
 
Design: Prospective, Randomized, Double-Blind, Placebo Controlled trial 
involving opiate-dependent patients undergoing lumbar spine surgery. 
Opioid dependence will be defined as greater than 60 mg oral morphine 
equivalents/day for greater than one week. Intraoperatively, patients will 
receive a 1 mg/kg dose of intravenous ketamine or saline with 15 minutes 
after induction of general anesthesia. Thereafter, a continuous infusion of 
0.20 mg/kg/hr ketamine with a maximum dose of 20 mg/hr or saline will be 
run to conclude at 48 hours after the end of the surgery (fascial closure). 
The primary outcome measure will be hydromorphone PCA usage during 
the first 72 hours postoperatively. Secondary outcome measures will be 
VAS pain scores at rest and with movement in PACU, 24 hr, 48 hr, 72 hr, 2 
week (post-op visit), 6 week follow-up visit, as well as, McGill Pain 
Questionnaire, Pain Catastrophizing Scale, and emotional distress surveys 
assessing depression and anxiety at preop/screening, postop and 6 week 
follow-up (PROMIS Emotional Distress-Anxiety Short Form, PROMIS 
Emotional Distress-Depression Short Form), as well as a Neuro-QOL Short 
Form v1.1 - Satisfaction with Social Roles and Activities . 
4. * Principal investigator: 
Jacques Chelly 
5. * Does the investigator have a financial interest related to this research? 
  
Yes 
No  
6. * Will an external IRB act as the IRB of record for this study? 
  
Yes 
No 

7. * What kind of study is this? 
Single-site study 
8. Attach the protocol: 
 
Sponsor/Multicenter protocol 
 
Investigator-initiated protocol 
 
Emergency Use Consent/ Protocol/ FDA Form 3926 
 
Exempt Application form 
  
Document 
Category Date 
Modified 
Document 
History 
View P01 Ketamine Protocol-
MG (003).docx(0.01) 
IRB 
Protocol 3/6/2019 History 
  
View: Pitt SF: Funding Sources (not integrated with Grants) 
Funding Sources 
1. * Indicate all sources of support: 
Internal funding 
View: Pitt SF: Study Team Members 
 
Study Team Members 
1. * Identify each person involved in the design, conduct, or reporting of the 
research (includes PI): 
Name 
Roles 
Affiliation 
Involved 
in 
Consent 
Qualifications 
Jacques 
Chelly 
Principal 
Investigator 
Pitt faculty 
yes 
Jacques E. Chelly, MD, PhD, MBA is 
a Professor of Anesthesia and 
Orthopedic Surgery at the University 
of Pittsburgh Medical Center. He has 
acted as p... 
 view all  

Trent 
Emerick 
Co-
investigator 
Pitt faculty 
yes 
Dr. Emerick is a anesthesiologist at 
Presbyterian Hospital and has 
participated in research studies 
Brian Gierl Co-
investigator 
Pitt faculty 
yes 
Dr. Gierl is an neuro-
anesthesiologist at Presbyterian 
Hospital and has been a co-
investigator on prior studies 
Michael 
Gold 
Co-
investigator 
Pitt faculty 
no 
Michael Gold, PhD is a professor in 
Neurobiology and Pain Research 
Center at the University of 
Pittsburgh. He is extensively 
knowledgeable in pain re... 
 view all  
John Hache Co-
investigator 
Pitt faculty 
yes 
Dr. Hache is an anesthesiologist at 
Presbyterian Hospital and has been 
a co-investigator on many research 
studies 
Caroline 
Kostishack 
Secondary 
Study 
Coordinator 
UPP/UPMC 
staff 
yes 
Caroline Stehle (nee Kostishack) is a 
clinical research coordinator and will 
be involved in the day to day 
implementation of the study protocol, 
incl... 
 view all  
Amy 
Monroe 
Primary Study 
Coordinator 
Pitt staff 
yes 
Ms Monroe is the Manager of the 
Clinical Trials Program for the 
Department of Anesthesiology & 
Perioperative Medicine. She will 
oversee aspects of th... 
 view all  
John 
Moossy 
Co-
investigator 
Pitt faculty 
yes 
John Moossy, MD, is a 
neurosurgeon at UPMC Presbyterian 
hospital. Participants will be 
recruited under Dr. Moossy's care. 
2. External team member information: (Address all study team members in 
item 1. above and leave this section blank) 
 
Name 
Description 
There are no items to display 
3. Have you, Jacques  Chelly, verified that all members of the research team 
have the appropriate expertise, credentials, training, and if applicable, child 

clearances and/or hospital privileges to perform those research procedures 
that are their responsibility as outlined in the IRB application? 
*   
Yes 
No 
View: Pitt SF: Study Scope 8.1 
 
Study Scope 
Check all that apply 
1. * Will this study actively recruit any of the following populations? 
 Adults with impaired decision-making capacity 
 
 
Children (under the applicable law of the jurisdiction in which the research will be 
conducted (<18 years for PA)) 
 Children who are Wards of the State 
 Employees of the University of Pittsburgh/UPMC 
 Medical Students of University of Pittsburgh as primary research group 
 Students of the University of Pittsburgh 
 Neonates of uncertain viability 
 Non-viable neonates 
 Non-English speakers 
 Nursing home patients in the state of Pennsylvania 
 Pregnant women 
 Prisoners 
 N/A 
2. * Will any Waivers be requested? 
 Waiver/Alteration of Consent 
 Waiver to Document Consent 
 Waiver/Alteration of HIPAA 
 Exception from consent for emergency research 
 N/A 
3. * Will this study involve any of the following? 

 Specimens 
 Honest Broker to provide data/specimens 
 Return of Results to Subjects or Others 
 Fetal tissue 
 N/A 
4. * Will Protected Health Information be collected? 
 Pitt medical records 
 UPMC medical records 
 Other Institutions’ medical records 
 N/A 
5. * Other Requests? 
 Deception (if not Exempt, also requires Waiver/Alteration of Consent) 
 Emergency Use / Single Patient Expanded Access 
 Placebo Arm 
 Withdraw from usual care 
 N/A 
6. * Determining Scientific Review: 
Department Scientific Review (DOD requires departmental review) 
* Choose the appropriate organization to conduct the scientific review: 
U of Pgh | School of Medicine | Anesthesiology 
7. * Has this study (or substantially similar study) been previously 
disapproved by the Pitt IRB or, to your knowledge, by any other IRB? 
  
Yes 
No 
Review the HRPO policy, if participating in research at the VA Pittsburgh 
Healthcare System or using funding from the VA 
8. * Does the study use an approved drug or biologic, use an unapproved 
drug or biologic, or use a food or dietary supplement to diagnose, cure, 
treat, or mitigate a disease or condition? 
  
Yes 
No 

9. * Does the study evaluate the safety or effectiveness of a device? 
  
Yes 
No 
10. 
* Is this application being submitted to convert an approved study 
from OSIRIS to PittPRO? (Tip Sheet) 
 
  
Yes 
No 
  
  
View: Pitt SF: Drugs 
Drugs 
1. * List all drugs, biologics, foods, and dietary supplements to be used in the 
study:  
  
Generic Name Brand Name Attachment Name 
View Ketamine 
Ketalar 
Ketamine package insert.pdf 
FDA exempt.pdf 
memo signed.pdf 
2. * Will the study be conducted under an investigational new drug 
application (IND) or radiation human subcommittee (HUSC)? 
  
Yes 
No  
3. Attach files: (such as IND, HUSC, or other information that was not attached for 
a specific drug)  
  Document 
Category 
Date Modified 
Document History 
 There are no items to display 
4. * Describe your plan to store, handle, and administer drugs so that they 
will be used only on subjects and be used only by authorized investigators: 
The study drug and saline placebo will be sourced by the Department of 
Pharmacy's Investigational Drug Service (IDS) at UPMC Presbyterian 
Hospital. The drug will be stored, handled and dispensed in accordance 
with Department of Pharmacy IDS guidelines to ensure the correct patient 
receives the drug and will only be administered under an investigator's 
order. . 

5. * Do you plan to utilize the UPMC Investigational Drug Service (IDS) to 
dispense the drug? 
  
Yes 
No 
View: Pitt SF: Local Site Documents 
 
Click Continue as this page was intentionally left blank. 
View: Pitt SF: Research Sites 
Research Sites  
1. Choose all sites that apply: 
UPMC 
2. * Select the UPMC sites where research will be conducted: 
Presbyterian 
Other UPMC Site- Specify below: 
3. List the Other UPMC sites: 
UPMC Neurosurgery Clinic 
4. Describe the availability of resources and the adequacy of the facilities to 
conduct this study: 
The PI has adequate time to dedicate to the completion of this project, and 
adequate staffing and support through the clinical research coordinators 
assigned to this project. Protected servers are available through UPMC and 
will be used for the creation and storage of protected health data collected 
in the course of this research. The PI has access to and will be supervising 
an electronic password-protected database. 
 
There is adequate and appropriate space for these research activities at 
Presbyterian Hospital where this research will be conducted. All research 
interventions/activities will be conducted in private patient care areas. This 
facility is adequate for the performance of all study procedures, and for 
handling emergency situations should they arise.  
 
Prospective subjects will be approached for consent in the UPMC 
Neurosurgery Clinic while doing their preoperative evaluations by a study 
coordinator and /or acute pain service member. 

View: Pitt SF: Study Aims 
 
Study Aims 
1. * Describe the purpose, specific aims, or objectives and state the 
hypotheses to be tested: 
The goal of this study is to determine whether comprehensive 
perioperative administration of the NMDA receptor antagonist ketamine can 
reduce postoperative pain tolerance and opiate consumption in chronic 
back pain patients undergoing spinal laminectomy/fusion when compared 
to saline placebo.  
 
Investigators hypothesize that administration of a ketamine infusion 
intraoperatively and for 48 hours postoperatively will significantly reduce 
postoperative opiate consumption and VAS pain scores in chronic back 
pain patients undergoing spinal laminectomy/fusion when compared to 
those in the placebo arm.  
 
 
2. * Describe the relevant prior experience and gaps in current knowledge 
including preliminary data. Provide for the scientific or scholarly 
background for, rationale for, and significance of the research based on 
existing literature and how it will add to existing knowledge: 
Patients with chronic pain are some of the most difficult to manage during 
the perioperative period, in part because they are often on large doses of 
opioids, rendering them relatively tolerant to the opioids used in the 
perioperative period. Several lines of evidence suggest that ketamine, 
administered intraoperatively, and/or post-operatively may be solution to 
this problem. Even more intriguingly, there is evidence to suggest that 
perioperative ketamine may have long term effects on opioid use. However, 
nearly all of the studies up to this point have investigated the short-term 
effects of ketamine on post-operative pain and opioid consumption. This 
pilot study will investigate the impact of intra-operative and post-operative 
ketamine on pain and opioid consumption six weeks after surgery and will 
support a larger NIH funded trial.  
 
Central Sensitization and the NMDA receptor: evidence from preclinical 
models of pain 
 
Seminal studies by Woolf and colleagues provided mechanistic insight into 
a phenomenon long appreciated by patients and clinicians alike: intense 
noxious stimulation results in an increase in pain from the site injury as 
well as from surrounding tissue well outside the injured tissue. The 

amplification and spread of the pain arising from the injured tissue is due, 
in at least in part to changes in the central nervous system in a process 
called central sensitization. Of particular relevance to the present proposal, 
the sensitization is critically dependent on spinal glutamatergic receptors, 
and in particular, the N-methyl-D-aspartate (NMDA) receptor (Wilcox, 1991; 
Davies, 1987; Dickenson, 1987) The NMDA receptor is a ligand gated ion 
channel which is activated by the endogenous agonist glutamate. The 
channel is subject to voltage-dependent block by endogenous Mg2+. 
Ketamine is a non-competitive antagonist of the NMDA receptor, binding to 
a site near the pore region that bind other antagonists such as MK-801 and 
memantine (Paolettia,2007). Blockade of the NMDA receptor by ketamine 
(Laird,1995) and other NMDA receptor antagonists (Fisher,2000) has been 
shown to inhibit development of hyperalgesia in several preclinical animal 
models of chronic pain.  
Opioid receptor agonists such as morphine are still the most efficacious 
medications available for the treatment of moderate to severe pain. One of 
the major limitations to the long term use of these compounds, however, is 
the development of tolerance. While the mechanistic details linking opioid 
and NMDA receptors have yet to be fully elucidated, there is compelling 
preclinical evidence that the development of tolerance depends on NMDA 
receptor activation: the development of tolerance is blocked by the 
administration of the non-competitive NMDA receptor blocker, MK-801 
(Marek, et al 1991). This potential role of the NMDA receptor in both 
mechanisms of tolerance formation and hyperalgesic states make it an 
attractive target for opioid-dependent patients undergoing surgical 
procedures. 
 
Clinical Studies of Ketamine in post-operative pain 
 
The analgesic and/or opioid sparing effects of ketamine has been studied 
in healthy subjects and pain patients including those suffering from 
glossopharyngeal neuralgia, postherpetic neuralgia, fibromyalgia muscle 
pain, stump and phantom limb pain, peripheral neuropathic pain, central 
neuropathic pain, chronic post-traumatic pain, pain due to arteriosclerosis 
obliterans (Fisher, 2000). The application of ketamine to the perioperative 
period as a “preemptive” or “preventive” analgesic has met with mixed 
results. Many of the earlier studies compared a preincisional with a 
postincisional dose of ketamine and saw no difference between the two. 
However a meta-analysis of 37 subsequent trials of the use of perioperative 
ketamine compared to placebo found that “ketamine in subanaesthetic 
dose is effective in reducing morphine requirements in the first 24 hours 
after surgery and also reduces postoperative nausea and vomiting” and 
“adverse effects are mild or absent.” (Bell, 2006). Twenty-seven of 37 trials 
found that perioperative ketamine reduced rescue analgesic requirements 
or pain intensity, or both. Ten trials found no significant difference between 
ketamine and placebo, three of which were considered non-sensitive. Of 

those that did find an effect, it was generally reported to give a 30-50% 
reduction of rescue analgesics. Another review that used VAS scores at 24 
hours after surgery as the primary outcome, and included an overlapping 
subset of studies did not find an overall significant effect of ketamine 
(Subramaniam, 2001). 
 
Dose Range and side effects 
 
There is an important difference in the dose range for ketamine’s 
anesthestic and analgesic effects. In the Cochrane review, the majority of 
studies investigated the effect of bolus dosing, although some included 
ketamine as part of a PCA. The doses used in these studies ranged from 
10-270 mg, all of which are considered to be subanesthetic in that they 
elicited rare or no side effects. There did not appear to be a benefit to 
increasing the total dose above 30 mg/24 hr (Bell, 2006). 
In more recent studies, Tucker et al found a clinical benefit through the co-
administration of ketamine with fentanyl at measured serum 
concentrations of 30–120 ng/ml, while side effects (visual hallucination, 
sedation) occurred at serum concentrations in excess of 200 ng/ml (Tucker, 
2008). Yamauchi et al found that a ketamine infusion of 2 mg/kg/day 
(approx. 5.4 mg/hr in 70 kg patient) yielded a serum concentration of 50 
ng/ml, and enhanced fentanyl PCA-induced postoperative analgesia 
(Yamauchi, 2005). Side effects that were observed in some of the previous 
studies were relatively rare and included some increased sedation, 
dysphoria, typically within the first 1-2 hours after a bolus dose 13. 
 
Application of ketamine to specific patient populations 
Most of the studies listed in the Cochrane and other reviews enrolled 
patients with no previous chronic pain syndrome. However, patients with 
chronic pain are some of the most difficult to manage during the 
perioperative period, in part because they are often on large doses of 
opioids prior to surgery. As a result, they are relatively tolerant to the 
doses of opioids used in the perioperative period. In one sense, chronic 
pain patients have already proven themselves to be sensitive to NMDA 
receptor activation, in that they already exhibit hyperalgesia, and a degree 
of opioid tolerance, both of which are NMDA receptor-dependent 
processes. The anecdotal experience of UPMC’s acute pain service is that 
many of the chronic pain patients respond well to a low dose of ketamine 
infusion in the postoperative period. One very recent study specifically 
investigated chronic back pain patients, and found that an intraoperative 
bolus and intraoperative infusion of ketamine resulted in lower total 
analgesic consumption and lower pain scores during post the immediate 
post-op period as well as 6 weeks after surgery (Loftus, 2010), suggesting 
that ketamine may also have long-term benefits in chronic pain patients 
undergoing surgery.  
 

Nearly all the studies up to this point have investigated a single 
administration or a brief intraoperative infusion of ketamine, and thus 
ketamine is likely eliminated from the system shortly after the conclusion 
of the surgery, potentially limiting the full efficacy of this therapy. NMDA 
receptors are likely to still be active in the post-operative period (i.e. end of 
surgery- 48 hours post-surgery), because of the continued activation of 
nociceptors as a result of processes activated by tissue damage. This is 
also the timeframe when tolerance to opioids is most problematic because 
it is when patients experience the most pain. Therefore, we predict that the 
use of ketamine during the post-operative period will not only enable better 
pain management over this time frame, but will have an even more 
significant long term impact on pain and opioid use. 
 
  
View: Pitt SF: Recruitment Methods 
Recruitment Methods 
* Will you be recruiting individuals for participation in this study? 
  
Yes 
No 
1. *  Describe who will be recruiting individuals for participation for this 
study: 
The Principal Investigator, Neurosurgeon Co-Investigators, and study 
coordinator 
2. * Select all methods to be used for recruitment: 
 Directly approaching potential subjects (in-person) 
 Email/Listserv/Electronic Mailing List 
 Flyers/Posters or Brochures 
 Letters sent to potential participants 
 Newspaper/Magazine advertisements 
 Pitt+Me 
 Radio/Television/Video announcements 
 Telephone scripts 
 Website/Social Media 
 Registries 

 Other 
3.  
 
*  Enter description of 'Other' method of recruiting: 
medical record review 
Neurosurgery Clinic Schedule 
4. * Provide details on your recruitment methods: 
Patients will be recruited from the UPMC Neurosurgery Clinic. The patient's 
medical record will be reviewed to assess for inclusion criteria including 
confirming that the patient is undergoing lumbar spine surgery of at least 
one level and no more than 4 levels, that the patient has chronic back pain 
(>3 months), is considered ASA 1-3, is of the age 18-65 and is opiate-
dependent, meeting both of the following criteria: 
a. Daily opiate use for at least 2 months 
b. Oral morphine equivalent of 60 mg/day or higher  
This medical record review to identify eligible candidates is minimal risk 
and that the rights and welfare of subjects will not be adversely affected 
The primary surgeon will identify patients who are prescreened via medical 
record to be eligible for inclusion, ask them if they would be interested in 
participating, and if so, the enrollment and consent process would be 
initiated. Participating neurosurgeons include Drs. Moossy, who will 
identify eligible patients. Informed consent will be performed by this 
Neurosurgeon, the PI, or other co-investigator in the study. Enrollment will 
be performed by the study coordinator and/or trained representative from 
the Acute Interventional Perioperative Pain Service (AIPPS). Enrollment will 
include review of eligibility, and detailed explanation of the study. 
5. * Describe all compensation/incentives offered to participants and timing 
of these offers: 
Participants will be compensated up to $100 for travel and parking 
expenses related to Pre-Op Visit ($50) and 6-Week Follow-up visit ($50) 
6. Recruitment materials: (attach all material to be seen or heard by subjects, 
including advertisements and scripts) 
  Document 
Category 
Date Modified 
Document History 
 There are no items to display 
View: Pitt SF: Study Design 
 
Study Design 

1. Total number of subjects to be enrolled at this site (enter -1 for chart 
reviews, banking, registries): 
20 
2. Describe and explain the study design: 
This study is being proposed as a pilot study to inform the feasibility and 
direction of a larger P01 NIH funded trial. 
3. Describe the primary and secondary study endpoints: 
Primary Outcome measure:  
 Pre- and post-surgical pain rating 
 Pre- and post-surgical opioid utilization (in morphine equivalent units in 
the PACU and post-operative period until discharge, at 14 days, and at 6 
weeks follow-up) 
 Pre- and post-surgical opioid analgesic efficacy 
 
Secondary outcome measures: 
 Mcgill Pain Questionnaire-Short Form 
 Pain Catastrophizing Scale 
 PROMIS Emotional Distress-Anxiety Short Form 
 PROMIS Emotional Distress-Depression Short Form 
 Neuro-QoL Short Form v1.1 - Satisfaction with Social Roles and 
Activities  
 Cold Pressor Test  
 
. 
4. Provide a description of the following study timelines: 
 
Duration of an individual subject's active participation: 
6 weeks 
Duration anticipated to enroll all subjects: 
5 months 
Estimated date for the investigator to complete this study (complete 
primary analyses):  
10/31/2019 
5. List the inclusion criteria: 
Patients undergoing lumbar spine surgery of at least one level, and no 
more than 4 levels. 
Patients with chronic back pain (>3 months) 
ASA 1-3 
Age 18-65 
Opiate-dependent, meeting both of the following criteria: 
1.Daily opiate use for at least 2 months 
2. Oral morphine equivalent of 60 mg/day or higher 

6. List the exclusion criteria: 
-Intolerance or known allergy to ketamine 
-History of increased intraocular pressure (> 22mmHg) 
-Uncontrolled hypertension (systolic blood pressure greater than or equal 
to 180, diastolic blood pressure greater than equal to 100) 
-Increased intracranial pressure (signs including:Behavior changes, -
Decreased consciousness, Headache, Lethargy 
-Neurological symptoms, including weakness, numbness, eye movement 
problems, and double vision, seizures, vomiting) 
History of psychosis 
Pregnancy 
Patients with significant liver disease (signs and symptoms of liver injury, 
such as discolored skin and eyes that appear yellowish, abdominal pain 
and swelling, Itchy skin that doesn't seem to go away, Dark urine color, 
Pale stool color, Bloody or tar-colored stool, Chronic fatigue, Nausea, Loss 
of appetite, with or without elevated LFTs: AST > 120 IU/ml, AP >130 IU/ml, 
and ALT >40 IU/ml) 
-Patients with exposure to CYP3A and / or CYP2B6 inhibitors, including the 
herbs and the over-the-counter compounds (list of drugs can be found at 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresou
rces/druginteractionslabeling/ucm093664.htm) 
 
7. Will children or any gender, racial or ethnic subgroups be explicitly 
excluded from participation? 
  
Yes 
No 
* Identify the subgroups and provide a justification:  
Presbyterian Hospital is an adult-only facility 
8. Describe the power analysis used and cite your method of statistical 
analysis. If a power analysis is not possible, thoroughly justify the sample 
size required for the study, including appropriate literature citation 
(alternatively provide page reference in attached protocol): 
This is a pilot to support a P01 program pilot application to the NIH, so the 
data will be analyzed mainly using descriptive statistics. Additional 
statistical analysis methods such as a 2-sample t test to compare 
significance between groups may also occur. 
View: Pitt SF: Research Activities 
 
Research Activities 

1. * Provide a detailed description of all research activities (including 
screening and follow-up procedures) that will be performed for the purpose 
of this research study. This description of activities should be complete 
and of sufficient detail to permit an assessment of associated risks. 
Patients will be recruited from the UPMC Neurosurgery Clinic. The primary 
surgeon will identify patients who would be eligible for inclusion, ask them 
if they would be interested in participating, and if so, the enrollment and 
consent process would be initiated. The participating neurosurgeon is Dr. 
Moossy, who has agreed to allow us access to his patients. Informed 
consent will be performed by Dr. Moossy, or the PI. Enrollment will be 
performed by the study coordinator and/or trained representative from the 
Acute Interventional Perioperative Pain Service (AIPPS). Enrollment will 
include review of eligibility, and detailed explanation of the study.  
 
Screening Visit: Approximately 1 hour 
After patients are enrolled into the study at the preoperative neurosurgery 
clinic, a number of forms will filled out by the subjects: McGill Pain 
questionaire-Short form (measures pain), pain medication review form, and 
the Pain Catastrophizing Scale (PCS) (assesses patient's ability to tolerate 
pain) PROMIS Emotional Distress-Anxiety Short Form (measures anxiety) 
and PROMIS Emotional Distress-Depression Short Form (measures 
depression), Brief Psychiatric Rating Scale (assesses psychiatric state of 
patient) and Neuro-QoL Short Form v1.1 - Satisfaction with Social Roles 
and Activities (assesses depression/anxiety when it comes to social roles) 
will also be completed.  
 
Pre-Operative Visit: Approximately 1.5 hrs 
 
The subject will be asked to come into the Aiken Medical Building, Suite 
407 on a date after the clinic visit but before their day of surgery for a Pre-
Operative Visit. Investigators will work with the subject to determine their 
opioid dose regimen, and the subject will be asked to come into the Aiken 
Medical Building thirty minutes before their opioid dose is due and will be 
asked to bring with them their upcoming dose of pain medication. Prior to 
taking their pain medication, the subject will then be administered a cold-
pressor pain sensitivity test. For this test, the subject will place their non-
dominant hand in a bowl of ice water up to the wrist. Pain threshold is 
defined as the time in seconds that is takes for the subject to first report 
the sensation of pain in the immersed hand. Pain tolerance is defined as 
the time in seconds that it takes for the subject to withdraw their hand from 
the ice water because it has become too uncomfortable for them to keep 
their hand immersed any longer. A cut-off of four minutes will be imposed 
to limit the potential for any tissue damage. At this time, the subject will be 
asked to remove their hand from the ice water, even if they say that they 
could keep their hand immersed for longer. Pain threshold, tolerance and 
cut-off will be recorded using a stop watch. Heart rate and blood pressure 

will be recorded before and after the cold-pressor test. Once the cold 
pressor test is completed, the McGill Pain Questionnaire will be 
administered. After this questionnaire is complete, the subject will take the 
dose of opioid medication they have brought from home and are scheduled 
to receive and will wait in the clinic for 30 minutes for the pain medication 
to take effect. Once the 30 minutes is complete, the cold-pressor test will 
be repeated, heart rate and blood pressure collected before and after, and 
McGill Pain Questionnaire will be administered again. Opioid-analgesic 
efficacy will be estimated by the change in pain threshold and tolerance 
observed after the opioid was consumed relative to initial assessment of 
pain threshold and tolerance. The subject will be compensated $50 for this 
pre-operative visit.  
 
Surgical Visit:  
 
Study groups: 
Patients will be randomized to one of the following groups: 
1. Intraoperative ketamine- post operative 48 hr ketamine infusion 
2. Intraoperative placebo (saline)- post operative placebo (saline) infusion 
 
Randomization will occur by a computer based system at a 1:1 ratio. The 
Investigational Drug Pharmacy will create the randomization log and IDS 
will randomize the subject independent of the research team. The study 
drug/placebo will look identical to maintain the blind for all clinicians and 
research staff involved.  
 
At the day of surgery, subjects will be seen by team members of the Acute 
Interventional Perioperative Pain Service preoperatively. Pregnancy will be 
assessed via medical record, as it is standard of care for these patients to 
take a pregnancy test day of surgery. Since the ketamine infusion will 
occur for 48 hours while patient is in the hospital, there is little risk of 
becoming pregnant during study drug treatment period 
 
Enrolled participants will receive a 1 mg/kg dose of intravenous ketamine 
or saline 15 minutes after induction of general anesthesia. Thereafter, a 
continuous infusion of 0.20 mg/kg/hr ketamine or saline with a maximum 
dose of 20 mg/hr will be run to conclude at 48 hours after the end of the 
surgery (fascial closure). 
 
A standardized general anesthesia protocol will be used by the hands-on 
provider. All drugs used intraoperatively, including total hydromorphone 
dose, will be collected from the electronic medical record. . 
 
The amount of narcotics and non-narcotic analgesics administered in the 
operative and postoperative period will be collected from the electronic 
chart from day of surgery until discharge. VAS pain scores will be collected 

from the PACU until discharge from the hospital.  
 
Pain will be monitored every four hours, except during the night when the 
participant is asleep. We will use a scale from 0-10, 0 being no pain, 5 being 
moderate pain and 10 being the worst imaginable pain. The participant will 
also be asked to score pain at its best and worst over the period since they 
were last asked.  
 
Post-Op Visit: Approximately 1 hour 
 
Patients will follow-up at Neurosurgery clinic at 10-14 days postoperatively. 
At this time daily opioid usage will be assessed and converted to morphine 
equivalents/24 hr. At this visit, the McGill Pain questionnaire-Short form, 
pain medication review form, and the Pain Catastrophizing Scale (PCS) 
(Sullivan, 1995). PROMIS Emotional Distress-Anxiety Short Form and 
PROMIS Emotional Distress-Depression Short Form, Brief Psychiatric 
Rating Scale and Neuro-QoL Short Form v1.1 - Satisfaction with Social 
Roles and Activities will also be completed by the participant.  
 
6-Week Follow-Up Visit: Approximately 1.5 hours 
 
The subject will be asked to come to the Aiken Medical Building, Suite 407 
approximately 6 weeks after their surgery for a 6-Week Follow-Up Visit. 
Investigators will work with the subject to determine their post-operative 
opioid dose regimen, and the subject will be asked to come in for the visit 
thirty minutes before their opioid dose is due and bring with them their 
upcoming dose of pain medication. Prior to taking their pain medication, 
the subject will then be administered a cold-pressor pain sensitivity test, in 
a manner identical to that use during the pre-operative assessment.In 
addition to the McGill Pain Questionnaire-Short form, a pain medication 
review form, the Pain Catastrophizing Scale (PCS) (Sullivan, 1995), the 
PROMIS Emotional Distress-Anxiety Short Form, the PROMIS Emotional 
Distress-Depression Short Form, Brief Psychiatric Rating Scale and Neuro-
QoL Short Form v1.1 - Satisfaction with Social Roles and Activities will also 
be completed. The subject will be compensated $50 for this 6-week follow-
up visit.  
 
 
 
2. Upload a copy of all materials used to collect data about subjects: (Attach 
all surveys, interview/focus group scripts, and data collection forms except 
for case report forms, SCID or KSADS): 

  
Document 
Category Date 
Modified 
Document 
History 
View Brief Psychiatric Rating Scale (0.01)  
Data 
Collection 3/6/2019 History 
View PROMIS v1.0 ED-Depression Short Form 
1.pdf(0.01) 
Data 
Collection 3/6/2019 History 
View PROMIS v1.0 ED-Anxiety Short Form 1.pdf(0.01) 
Data 
Collection 3/6/2019 History 
View Pain%20catastrophizing%20scale-1.docx(0.01) 
Data 
Collection 3/6/2019 History 
View 
Neuro-QOLv1.1-
SatisfactionwithSocialRolesandActivitiesSF_03-06-
2014.pdf(0.01)  
Data 
Collection 3/6/2019 History 
View Medications- questionaire.doc(0.01) 
Data 
Collection 3/6/2019 History 
View Mcgill pain questionaire.docx(0.01) 
Data 
Collection 3/6/2019 History 
3. * Will blood samples be obtained for research purposes? 
  
Yes 
No 
  
View: Pitt SF: Consent Process 
Consent Process 
Enter N/A in response to the following questions if a Waiver of Consent is requested for all 
research activities or if no subjects are being enrolled. 
1. * Indicate where the consent process will take place and at what point 
consent will be obtained: 
Patients will be recruited from the UPMC Neurosurgery Clinic. The primary 
surgeon will identify patients who would be eligible for inclusion, ask them 
if they would be interested in participating, and if so, the enrollment and 
consent process would be initiated. Participating neurosurgeons include 
Drs. Moossy, who will identify eligible patients. Informed consent will be 
performed by this Neurosurgeon, the PI, or other co-investigator in the 
study. Enrollment will be performed by the study coordinator and/or trained 
representative from the Acute Interventional Perioperative Pain Service 

(AIPPS). Enrollment will include review of eligibility, and detailed 
explanation of the study. 
2. * Describe the steps that will be taken to minimize coercion and undue 
influence, including assurance that there is sufficient time for subjects to 
make an informed decision: 
In order to minimize the possiblity of coercion or undue influence, the 
patients will be first informed that the choice of particpation in the study is 
totally voluntarily in nature, and they will receive a standard of care when 
they decide not to participate in the study. Prospective patients will be 
encouraged to ask questions and to discuss the study with others during 
the consent process. Then, they will be assured that after participation in 
the study, they will receive either ketamine or placebo in a randomized 
fashion if they participate in the study. Informed consent will occur in the 
neurosurgery clinic during their pre-surgical clinic visit. 
3. For studies that involve multiple visits, describe the process to ensure 
ongoing consent: 
At each visit, the subjects will be asked if they have any questions and will 
be reminded about the goals and objectives of the study. The subjects will 
also be reminded that they can withdraw from the study at any time. 
4. * Steps to be taken to ensure the subjects’ understanding: 
Individuals will be provided with full explanation of study-related goals and 
procedures. Questions will be answered from the patient as well as their 
family members as necessary. Patients will be given as much time as 
necessary to read the consent form and ask questions. 
5. * Are you requesting an exception to the IRB policy related to the informed 
consent process: 
  
Yes 
No 
View: Pitt SF: Consent Forms 
 
Consent Forms  
1. Consent Forms: 
  
Document 
Category 
Date 
Modified 
Document 
History 
View Consent draft_Version 
4.3.19.docx(0.03) 
Consent 
Form 
4/3/2019 
History 

2.  
Refer to the following templates and instructional documents: 
 
Guidance - Consent Wording 
 
Template - Consent Document - Short Form 
 
HRP-090 - SOP - Informed Consent Process for Research   
 
HRP-091 - SOP - Written Documentation of Consent   
  
View: Pitt SF: Medical Records 
Medical Records 
1. You are required to submit this study to the Research Informatics Office, Health 
Record Research Request (R3). Per UPMC Policy HS-RS0005, all research projects 
that access or involve UPMC electronic protected health information (e-PHI) must 
be submitted to R3, with the exception of clinical trials that are contracted through 
the UPMC Office of Sponsored Programs and Research Support (OSPARS). 
Complete the R3 intake form available at http://rio.pitt.edu/services. An R3 
representative will conduct a review. You will be notified once your R3 review is 
complete or if anything further is needed. 
* Describe the protected health information that will be collected from the 
covered entity and/or the research derived information that will be 
placed into the medical records: 
Patient demographics and medical history will be collected from the 
medical record 
 
The amount of narcotics and non-narcotic analgesics administered in the 
operative and postoperative period will be collected from the electronic 
chart from day of surgery until discharge. VAS pain scores will be collected 
from the PACU until discharge from the hospital. 
View: Pitt SF: Electronic Data Management 
Electronic Data Management 
 
1. * Will only anonymous data be collected (select NO if identifiers will be 
recorded at anytime during the conduct of the study)? 
  
Yes 
No 

Select all identifiers to be collected during any phase of the research 
including screening: 
 
Name: 
E-mail address: 
Social security #: 
Phone/Fax #: 
Account #: 
Medical record #: 
Certificate/license 
#: 
 
  
 
  
 
Internet Protocol (IP) Address: 
Web Universal Resource Locators (URLs): 
Social security # (for Vincent payment only): 
Full face photo images or comparable 
images: 
 
Health plan beneficiary #: 
Device identifiers/serial numbers: 
Vehicle identifiers/serial #/license plate #: 
Biometric identifiers, finger and voice 
prints: 
 
 
* 
a: Will you be collecting any of 
the following location data: 
geographic subdivisions smaller 
than a State such as street 
address, city, county, precinct, 
zip, geocodes, etc.? 
  
  
Yes 
No 
* 
b: Will you be collecting any date 
information such as birth date, 
death, admission, discharge, 
date of surgery/service? 
  
Yes 
No 
c: List any other unique 
identifying numbers, 
characteristics or codes related 
to an individual that are to be 
collected: 
* 
d: Provide a justification for 
recording Social Security 
numbers including why it's 
required, where it's stored, how 
it's protected and who will have 
access: 
Will be collecting SSN's only for Vincent 
payment, only the PI and coordinator will 
have access to the SSN's and only for the 
purpose of setting up Vincent payments. 
SSN's will be collected separately from 
the study data and destroyed after 
Vincent payment has been set up. 
 

* 
For ALL identifiable data collected, will 
you be coding the data by removing the 
identifiers and assigning a unique study 
ID/code to protect the identity of the 
participant? 
  
Yes 
No 
* Will the data be HIPAA de-identified? 
  
Yes 
No 
* Briefly describe your plan to store coded 
data separately from the identifiable data: 
To protect against the 
possibility of breach of 
confidentiality, all data collected 
will be identifiable only by an 
unique subject ID number, and 
no personal identifiers will be 
stored with the data. Linkage 
files identifying subjects will be 
stored only in the UPMC server 
and will be linked to the 
physical record with a subject 
code. Physical records will be 
kept in locked files accessible 
only by study staff; electronic 
data will be handled and 
protected as described above 
on the UPMC server. 
2. * Will sensitive data be collected (e.g., protected health information, mental 
health, medications, drug/alcohol use, illegal behaviors)? 
  
Yes 
No 
3. * Select all locations where data will be stored or accessed (including 
e.g., personal / employer laptop or desktop):  
  
Storage Device 
Description Identifiable 
Data 
Sensitive 
Data 
De-
Identified/Anonymous 
Data 
View 
UPMC owned 
desktop, laptop or 
other device 
  
no 
no 
no 
View Server: UPMC 
Managed Server 
  
yes 
yes 
yes 
4. * Select all technologies being used to collect data or interact with 
subjects: 

N/A 
View: Pitt SF: Data Safety and Monitoring 
 
Data Safety and Monitoring 
1. * Describe your plan to periodically evaluate the data collected regarding 
both harms and benefits to determine whether subjects remain safe.  The 
plan might include establishing a data monitoring committee and a plan for 
reporting data monitoring committee findings to the IRB and the sponsor: 
The proposed study will use the FDA definition of adverse events (AE) and 
serious adverse events (SAE). Any SAE, which is unexpected and related 
to study intervention, will be reported immediately to the IRB and will be 
followed by an additional letter detailing the nature of the SAE. In the event 
that a participant either withdraws from the study or the investigators 
decide to discontinue a participant due to a SAE, the participant will be 
monitored by the co-PIs until (a) a resolution is reached (e.g., the problem 
has resolved or stabilized with no further change expected), (b) the SAE is 
determined to be clearly unrelated to the study intervention, or (c) the SAE 
results in death. Outcomes of SAEs will be regularly reported to the IRB 
and the sponsor. A summary of the SAEs that occurred during the previous 
year will be included in the annual progress report as well as in the annual 
IRB renewal. 
If an unexpected adverse event occurs, the investigators will re-assess the 
risk-benefit ratio of the study and submit any modifications deemed 
necessary to the IRB for approval. If necessary, protocol refinement will 
occur to address safety concerns and/or adjustments necessary based on 
laboratory refinement, practitioner and/or patient acceptability, or other 
issues that may be uncovered. 
 
Data will be continuously monitored by study coordinator and PI when 
subjects are being actively treated and are in the hospital. The PI and study 
coordinator will review questionnaire and cold-pressor data weekly. 
2.   * Describe your plan for sharing data and/or specimens: 
In the future, the investigators may decide to share data with other 
investigators both within and outside of this institution. If that were to 
occur, we would de-identify all of the information prior to sharing any data 
in this way. 
3. If any research data is collected, stored, or shared in a paper format, 
address what precautions will be used to maintain the confidentiality of the 
data: 
Paper-based records will be kept in a secure location, computer-based files 
will be available to personnel involved in the study through access 

privilege, whenever possible identifiers will be removed from study-related 
information, patients' computer medical information will only be available 
through password access.  
 
Identifiable data will be kept in a single encrypted file on the shared (z:) 
drive behind the UPMC firewall. All other study-related data (such as paper 
records and data for analysis) will have all identifiers removed. 
View: Pitt SF: Risk and Benefits 
 
Risk and Benefits 
1. *  Enter all reasonably foreseeable risks, discomforts, hazards, or 
inconveniences to the subjects related to subjects’ participation in the 
research: 
View 
Research Activity 
Collection of information from medical records   
Common Risks 
No Value Entered  
Infrequent Risks 
Breach of confidentiality  
Other Risks 
No Value Entered  
View 
Research Activity 
completion of questionnaires   
Common Risks 
No Value Entered  
Infrequent Risks 
feelings of frustration, embarrassment or boredom  
Other Risks 
No Value Entered  
View 
Research Activity 
low dose ketamine infusion   
Common Risks 
No Value Entered  
Infrequent Risks 
Allergic Reaction (rare) Blurred vision(infrequent) Confusion (infrequent) 
Drowsiness (infrequent) Increased or decreased blood pressure or heart rate 
(infrequent) Mental or mood changes (infrequent) Nausea and vomiting 
(infrequent) Dreams, hallucinations and delirium (infrequent) Liver injury (rare)   
Other Risks 
With respect to the risk of liver injury, there have been reports of reversible, 
elevated liver enzymes associated with long term, repetitive use of high dose 
ketamine, although there are currently no reports of liver injury associate with 
low dose ketamine, which is used in this study. That being said, you are 
instructed to notice the following signs and symptoms of liver injury, and 

report to physicians with the information of previous exposure of ketamine 
infusion: • Discolored skin and eyes that appear yellowish • Abdominal pain 
and swelling • Itchy skin that doesn't seem to go away • Dark urine color • Pale 
stool color • Bloody or tar-colored stool • Chronic fatigue • Nausea • Loss of 
appetite   
View 
Research Activity 
cold pressor test  
Common Risks 
No Value Entered  
Infrequent Risks 
Excessive painful sensation (rare) tissue damage (rare)  
Other Risks 
No Value Entered  
2. *  Describe the steps that will be taken to prevent or to minimize risks: 
Experimental Interventions: 
 
Participants will receive ketamine infusion at the in-patient units. Should 
any complications associated with the medication occur, emergency cart is 
readily available at the units. Acute Interventional Perioperative Pain 
Service (AIPPS), which is responsible for the participants' postoperative 
pain management, is 24/7 available to address any associated issues.  
 
All aspects of patients' analgesic care, including the management of low-
dose ketamine infusion, will be administered under the consultation of the 
acute Interventional Perioperative Pain Service, which routinely uses these 
infusions in the managment of perioperative pain in opioid dependent or 
difficult to treat patients. This service is on call 24 hours/day. Ketamine 
infusions will only be administered to inpatients who are on floors where 
nursing staff has undergone training in the managment and administration 
of low dose ketamine infusions.  
 
Patients will be instructed to notice the signs and symptoms of liver injury 
and report to medical staff about previous exposure to ketamine infusion. 
Patients will also be followed up for mental status change with Brief 
Psychiatric Rating Scale.  
 
If the subject is particularly sensitive to the cold pressor test, they will be 
encouraged to move hand from the ice as soon as they feel any pain 
sensation. There is a four-minute limit on the test to reduce any risk of 
tissue damage. The participant will be made aware that they can refuse the 
cold pressor test should they choose.  
 
Investigators who will access the identifiable medical records already have 
normal clinical access to all necessary records, as granted by the privacy 
office for job-related needs. Thus, only HIPAA trained research staff will be 
handling this information and this information will be stored in a locked 

database protected by the UPMC firewall. Additionally, all data generated 
under this protocol will be monitored and maintained by the principal 
investigator. Any databases that contain identifiable information will be 
stored on a departmental drive on the UPMC network created for the 
principal investigator, and all data will be deidentified according to the 
HIPPA "safe harbor" guidelines prior to statistical analysis.  
 
Pregnancy is being assessed via a medical record review. Since the 
ketamine infusion will occur for 48 hours while patient is in the hospital, 
there is little risk of becoming pregnant during study drug treatment 
period. 
 
The follow up contact will be made by trained physicians. 
3. Financial risks - will the subject or insurer be charged for any research 
required procedures? 
  
Yes 
No 
4. Describe the steps that will be taken to protect subjects’ privacy: 
Research intervention will be conducted in a private room with the patient, 
collected information will be limited to that which is necessary for the goals 
of the research study, access to the patient's private information will be 
limited to those involved in the patient's medical care. 
5. What steps will be taken in the event that a clinically significant, 
unexpected disease or condition is identified during the conduct of the 
study: 
The patient's primary medical team will be immediately notified of the 
unexpected, clinically significant condition. The patient's clinically 
significant medical condition will be managed accordingly. If any of the 
clinically significant medical condition is related to the study, then the 
patient's participation in the study will be re-evaluated, with the possibility 
of the patient being withdrawn from the study if this leads to the resolution 
of the clinically significant medical condition 
6. Describe the potential benefit that individual subjects may experience from 
taking part in the research or indicate if there is no direct benefit. Do not 
include benefits to society or others: 
Patients with chronic pain and opioid dependence may experience better 
analgesia in the postoperative period. There is no guaranteed direct benefit 
to participants. 
7. Do you anticipate any circumstances under which subjects might be 
withdrawn from the research without their consent? 
  
Yes 
No 

*  Describe the circumstances and any procedures for orderly termination: 
Subject's failure to follow study procedures  
Severe allergic reaction to study drug 
8. Describe procedures that will be followed when subjects withdraw from the 
research, including partial withdrawal from procedures with continued data 
collection and data already collected: 
If a participant withdraws from research, follow up will cease but data 
previously collected may still be used in analysis. 
View: Pitt SF: Placebo Arm 
Placebo Arm 
1. *  Is there a commonly used diagnostic/treatment approach that is 
currently recognized as being effective for the proposed subjects' disease 
or condition, and that will be withheld from subjects assigned to the 
placebo arm of this research study: 
No - subjects assigned to the placebo and experimental arms of the 
research study will continue to undergo a commonly used 
diagnostic/treatment approach 
2. Describe the commonly used diagnostic/treatment approaches that will be 
withheld from subjects assigned to the placebo arm of this research study: 
No commonly-used treatment approach will be withheld from the subjects 
assigned to the placebo arm of this research study. 
3. Is enrollment into this study limited to individuals in whom the commonly 
used diagnostic/treatment approaches are known to be ineffective or 
intolerable? 
Enrollment into this study is limited to individuals who are opioid tolerant 
and therefore difficult to treat regarding post operative pain management. 
Subjects in both arms will receive the same standard of care treatment for 
post-operative pain management. 
4. Provide a scientific justification for the placebo-control arm of this 
research study: 
The placebo-control arm will allow for the clinicians to remain blinded to 
the treatment allocation of participants which will greatly improve the value 
of the pilot. This research is intended to develop an intervention 
(continuous, low dose ketamine infusion for 48 hours post-op) that can be 
implemented in the population from which trial participants are drawn 
(Opioid tolerant patients). Further, this trial does not require participants to 
forgo treatment they would otherwise receive 

5. How long will subjects participate in the placebo arm?  Justify why this 
duration is necessary: 
Subjects randomized in the placebo arm will receive the saline placebo in 
the exact same fashion as the intervention arm--intraoperatively and then 
for 48 hours post-operatively. 
6. How frequently will the subject's condition or disease be monitored and 
compare that to the frequency of monitoring associated with standard care 
for this disease/condition? 
Participants in both groups will be monitored by the research team while in 
the hospital for incidence of adverse events, so they will be monitored 
more frequently than the standard of care. 
7. What specific endpoints will result in discontinuing a subject's 
participation due to worsening of the subject's disease or condition? 
The same stopping criteria for the intervention arm will be applied to the 
placebo arm, because clinicians will be blinded to treatment allocation. 
8. What is the risk to subjects who receive no active treatment for their 
disease or condition while in the placebo arm? 
Subjects in the placebo arm will still have their post-operative pain 
managed as per standard of care for this population at Presbyterian 
Hospital. 
9. Describe the planned involvement of a 'contact person' who interacts with 
the subject on a regular basis and who will notify the investigators 
immediately of any problems related to the subject's disease or condition: 
The study coordinator (Amy Monroe) will be monitoring the subjects on a 
regular, daily basis and will notify the PI of any problems related to the 
subject's condition. 
Note: The involvement of the contact person must also be addressed in the 
consent form 
View: Pitt SF: Conflict of Interest 
Conflict of Interest 
  
1. * Is this an FDA Covered Clinical Study? 
  
Yes 
No 
Answer YES if it is: 

 
A study of a drug or device in humans to be submitted in a marketing 
application or reclassification petition that the applicant or FDA relies on to 
establish that the product is effective (including studies that show 
equivalence to an effective product); or  
 
A study in which a single investigator makes a significant contribution to 
the demonstration of safety.  
Do NOT include:  
 
phase l tolerance studies or pharmacokinetic studies;  
 
clinical pharmacology studies (unless they are critical to an efficacy 
determination);  
 
large open safety studies conducted at multiple sites;  
 
treatment protocols; or  
 
parallel track protocols.  
2. * Does this study involve a Non-Significant Risk Device and you anticipate 
including the results as part of any type of submission to the FDA for 
approval of this device? 
  
Yes 
No 
3. * Does any investigator involved in this study have a financial interest as 
the inventor or developer of intellectual property that is being evaluated or 
developed in this study including, but not limited to, a patent, trademark, 
copyright or licensing agreement? 
  
Yes 
No 
4. * Is this study funded in part or whole by a PHS Agency? 
  
Yes 
No 
5. * Does any investigator involved in this study (select all that apply): 
 
 
A. Have a financial interest (aggregated value of equity and remuneration during 
the past or next twelve months) in a publicly-traded entity that either sponsors this 
research or owns the technology being evaluated or developed that exceeds a 5% 
ownership interest or a current value of $10,000? 
 
 
B. Receive remuneration (during the past or next twelve months) from a non-
publicly traded entity that either sponsors this research or owns the technology 
being evaluated or developed that exceeds $10,000? 
 
 
C. Have equity in a non-publicly traded entity that either sponsors this research or 
owns the technology being evaluated or developed? 
 
 
D. Have rights as either the author or inventor of intellectual property being 
evaluated or developed in this research and for which you are receiving royalties, 

milestone fees, or other proceeds that have or will exceed $10,000 in any 12-
month period (include payments through the University of Pittsburgh, the Veterans 
Administration Pittsburgh Healthcare System, UPMC, and University of Pittsburgh 
Physicians)? 
 
 
E. Have an officer or management position with a company that either sponsors 
this research or owns the technology being evaluated or developed? 
 
 
F. Receive compensation of any amount when the value of the compensation 
would be affected by the outcome of this research, such as compensation that is 
explicitly greater for a favorable outcome than for an unfavorable outcome or 
compensation in the form of an equity interest in the entity that either sponsors this 
research or owns the technology being evaluated or developed? 
 
 
None of the above options apply and there are no other financial conflicts of 
interest in the conduct of this research. 
6. Provide the name of the investigator(s) and describe the nature of the 
Significant Financial Interest(s): 
 
View: Pitt SF: Ancillary Reviews 
 
Ancillary Reviews  
1. Ancillary reviews or notifications selected below are required based on 
previous answers to questions. If a selection is incorrect, return to the 
appropriate page and adjust the answers to questions on that page:  
  Conflict of Interest (COI) 
  Clinical and Translational Research Center (CTRC) 
  Data Security 
  Honest Broker 
  UPMC Investigational Drug Service 
  Pitt Medical School Review 

  Office of Investigator-Sponsored IND & IDE 
Support (O3IS) 
  RCCO Business Manager (required for industry 
sponsored studies) 
  Religious Directives 
  Scientific Review 
  Health Record Research Request (R3) (required if 
using UPMC clinical data and authorization for other 
UPMC data sources for research) 
  UPMC Office of Sponsored Programs and 
Research Support (using UPMC facilities and/or UPMC 
patients during the conduct of the study) 
2. Additional ancillary reviews the PI may choose to include as needed for the 
research: 
  Human Stem Cell Oversight (hSCRO) 
  Institutional Biosafety Committee (IBC)(study 
involves deliberate transfer of recombinant or synthetic 
nucleic acid molecules) 
  Radioactive Drug Research 
Committee (RDRC)(study involves the evaluation or use 
of procedures that emit ionizing radiation) 
View: Pitt SF: Clinical Trials 
Good Clinical Practice (GCP) Training 

1. * Regardless of funding source, is this study a clinical trial (as defined by 
the NIH)? 
  
Yes 
No 
ClinicalTrials.gov Information 
Visit the University of Pittsburgh Office for ClinicalTrials.gov website or 
contact ctgov@pitt.edufor further information.   
2. 
* Was this study registered, or will it be registered, on ClinicalTrials.gov? 
  
Yes 
No 
3. 
* Is the University of Pittsburgh or UPMC the Sponsor Organization for this 
study record? 
  
Yes 
No  
* Who will be the Responsible Party for this study record? 
 
Principal Investigator of this IRB application 
View: Pitt SF: Supporting Documents 
Supporting Documents 
1. Attach any additional supporting documents not previously uploaded. 
Name the documents as you want them to appear in the approval letter: 
  Document 
Category 
Date Modified 
Document History 
 There are no items to display 
View: Pitt Create 
 
Add Drug Information 
1. Select the drug: 
Ketamine  
  
If you cannot find the drug in the list above, enter 
its information here: 
Generic name: 

 
 
Brand name: 
 
2. *  Purpose of their use: 
KETALAR (generic: ketamine) is a rapid-acting general anesthetic 
producing an anesthetic state characterized by profound analgesia, normal 
pharyngeal-laryngeal reflexes, normal or slightly enhanced skeletal muscle 
tone, cardiovascular and respiratory stimulation, and occasionally a 
transient and minimal respiratory depression. The mechanism of action is 
primarily due to antagonism of N-methyl-D-aspartate (NMDA receptors) in 
the central nervous system. 
3. *  FDA status: 
Drug being used "off-label" 
4. Attach files related to this drug: 
  
Document 
Category 
Date 
Modified 
Document 
History 
View memo 
signed.pdf(0.01)  
Drug 
Attachment 2/12/2019 History 
View FDA exempt.pdf(0.01) Drug 
Attachment 2/12/2019 History 
View Ketamine package 
insert.pdf(0.01) 
Drug 
Attachment 2/12/2019 History 
5. Attachments may include a copy of the package insert, 
investigator brochure, product labeling, or verification 
of any IND number. 
View: Pitt Create 
Add Storage Information 
 
1. *  Select a Storage Type: 
UPMC owned desktop, laptop or other device 
2. Description: 
 

3. *  Will identifiable data be stored in this location? 
  
Yes 
No 
4. *  Will sensitive data be stored in this location? 
  
Yes 
No 
5. Will de-Identified or anonymous data be stored in this location? 
  
Yes 
No 
6. *  Is anti-virus software installed and up to date on all devices and are the 
operating systems kept up-to-date on all devices? 
  
Yes 
No 
7. Provide additional information as needed: 
 
View: Pitt Create 
 
Add Storage Information 
 
1. *  Select a Storage Type: 
Server: UPMC Managed Server 
2. Description: 
 
3. *  Will identifiable data be stored in this location? 
  
Yes 
No 
4. *  Will sensitive data be stored in this location? 
  
Yes 
No 
5. Will de-Identified or anonymous data be stored in this location? 
  
Yes 
No 
6. Provide additional information as needed: 
 

View: Pitt Risk 
 
Risk 
1. * Research Activity: 
Collection of information from medical records 
2. Common Risks: 
 
3. Infrequent Risks: 
Breach of confidentiality 
4. Other Risks: 
 
View: Pitt Risk 
 
Risk 
1. * Research Activity: 
completion of questionnaires 
2. Common Risks: 
 
3. Infrequent Risks: 
feelings of frustration, embarrassment or boredom 
4. Other Risks: 
 
View: Pitt Risk 
 
Risk 
1. * Research Activity: 
low dose ketamine infusion 

2. Common Risks: 
 
3. Infrequent Risks: 
Allergic Reaction (rare) Blurred vision(infrequent) Confusion (infrequent) 
Drowsiness (infrequent) Increased or decreased blood pressure or heart 
rate (infrequent) Mental or mood changes (infrequent) Nausea and vomiting 
(infrequent) Dreams, hallucinations and delirium (infrequent) Liver injury 
(rare) 
4. Other Risks: 
With respect to the risk of liver injury, there have been reports of 
reversible, elevated liver enzymes associated with long term, repetitive use 
of high dose ketamine, although there are currently no reports of liver 
injury associate with low dose ketamine, which is used in this study. That 
being said, you are instructed to notice the following signs and symptoms 
of liver injury, and report to physicians with the information of previous 
exposure of ketamine infusion: 
• Discolored skin and eyes that appear yellowish 
• Abdominal pain and swelling 
• Itchy skin that doesn't seem to go away 
• Dark urine color 
• Pale stool color 
• Bloody or tar-colored stool 
• Chronic fatigue 
• Nausea 
• Loss of appetite 
 
View: Pitt Risk 
 
Risk 
1. * Research Activity: 
cold pressor test 
2. Common Risks: 
 
3. Infrequent Risks: 
Excessive painful sensation (rare)  
tissue damage (rare) 
4. Other Risks: