Conditions: Opioid Dependence Chronic Pain
Keywords: Ketamine Lumbar Spine Surgery Opioid Tolerant
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1
Healthy volunteers: no

Brief summary:
The goal of this study is to determine whether comprehensive perioperative administration of the N-methyl-D-aspartate (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

Opioid dependence will be defined as daily opioid use (2 or more doses per day) for a period of two-months or longer. 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 24 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 .

Detailed description:
Patients will be recruited from the University of Pittsburgh Medical Center (UPMC) Neurosurgery Clinic and Operating Room Schedule. 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 neurosurgeons include Dr. Okonkwo and Dr. Hamilton, who have agreed to allow us access to their patients. Informed consent will be performed by the surgeon 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:

After patients are enrolled into the study at the preoperative neurosurgery clinic, a number of forms will be filled out by the participants: McGill Pain questionaire-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.

Pre-Operative Visit:

The participant 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 participant to determine their opioid dose regimen, and the participant 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 participant will then be administered a cold-pressor pain sensitivity test. 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 participant 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.

Surgical Visit:

At the day of surgery, participants will be seen by team members of the Acute Interventional Perioperative Pain Service preoperatively. Patients will be randomized into the Ketamine Group or the Placebo Group.

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 chart.

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. Visual Analogue Scale (VAS) pain scores will be collected.

Post-Op Visit:

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: 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:

The participant will be asked to come to the Aiken Medical Building, Suite 407 approximately 6 weeks after their surgery. Investigators will work with the participant to determine their post-operative opioid dose regimen. Prior to taking their pain medication, the participant 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.

Arms:
arm 1: Participants will receive a 1 mg/kg dose of intravenous ketamine 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 will be run to conclude at 48 hours after the end of the surgery (fascial closure). arm 2: Participants will receive a 1 mg/kg dose of intravenous saline 15 minutes after induction of general anesthesia. Thereafter, a continuous infusion of 0.20 mg/kg/hr 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).

Interventions: intervention 1: Ketamine intervention 2: Placebo Comparator
Intervention descriptions: intervention 1: Intraoperative ketamine and post operative 48 hour ketamine infusion with a standardized general anesthesia protocol. intervention 2: Participants will receive a 1 mg/kg dose of intravenous saline 15 minutes after induction of general anesthesia. Thereafter, a continuous infusion of 0.20 mg/kg/hr 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)

Protocol document:
ICF_002.pdf: 
 
 
 
 
 
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 
Informed Consent Form – Approved 01/04/2022 
 


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Department of Anesthesiology
CONSENT TO ACT AS A PARTICIPANT IN A RESEARCH STUDY
TITLE: Perioperative Ketamine in Opioid-Tolerant Patients Undergoing Spine 
Surgery: A Randomized, double-blind, placebo-controlled trial
PRINCIPAL INVESTIGATOR:
Jacques E. Chelly, MD, PhD, MBA
532 South Aiken Avenue, Suite 407
Pittsburgh, PA 15232
CO-INVESTIGATORS:
David Kojo Hamilton, MD
David Okonkwo, MD, PhD
Trent Emerick, MD
Brian Gierl, MD
John Hache, MD
SOURCE OF SUPPORT:
P01 Pilot Program 
Why is this research being done?
Individuals with chronic, or constant reoccurring, pain tend to need large doses of 
opioids (strong pain medications) to get through their daily lives. Overtime, however, 
they can develop opioid tolerance, or immunity, which makes the opioids less effective. 
These individuals can have, due to their opioid use, difficultly managing their pain during 
surgery and throughout their recovery. Standard of care for spine surgeries requires 
doctors to prescribe opioids to reduce post-surgical pain. Unfortunately, these 
individuals suffering from chronic pain and opioid tolerance tend to need larger doses of 
opioids than average for their pain management. However, there is evidence to suggest 
that ketamine, administered during surgery and/or during recovery may be the solution 
to this problem. There is also evidence to suggest that ketamine used in surgery and 
throughout recovery may have long term effects on individual opioid use. However, 
nearly all of the studies up to this point have investigated the short-term effects of 
ketamine on post-surgical pain and opioid use. This pilot study (small-scale preliminary 
research) will investigate the impact of surgical and recovery use of ketamine on pain 
and opioid use six weeks after surgery and will support a larger National Institute of 
Health (NIH) funded research trial.


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Who is being asked to take part in this research study?
You are being asked to participate in a research study because you are scheduled to 
have cervical, thoracic, or lumbar spine surgery and you receive opioid prescriptions for 
back pain.  Approximately 20 subjects will be screened and asked to participate in this 
study.  The length of time that you would be asked to be a part of this study is up to 6 
weeks.
You will be identified as a potential participant for this study during your visit to the UPMC 
Neurosurgical Clinic. If you are interested in learning more about the study, you will be given 
this consent form and asked to review it at home. You will receive phone call from research 
staff in the days following your clinic visit to determine if you would like to come in to the 
Posner Pain Research Clinic to provide consent and be enrolled in the study. If you think 
would like to provide consent to participate in the study, the study investigator will ask you 
your opioid dose regimen to determine a good time to come to the Posner Pain Research 
Clinic to review and sign the informed consent with a study doctor. After you discuss the study 
with the study doctor and sign the informed consent, you will undergo Screening Visit 
procedures.
What procedures will be performed for research purposes?
Screening Visit:
The screening process will be completed by the investigators with the Anesthesia 
Department. 
You will be asked to come to the Posner Pain Clinic in the Aiken Medical Building on a 
date after your clinic visit but before your day of surgery for this Screening Visit. The 
address for the Posner Pain Clinic is 532 South Aiken Avenue, Suite 407, Pittsburgh PA 
15232. At this screening visit you will be asked to review your current pain medication 
use and complete seven health questionnaires.
In addition to reporting on your current pain medications and completion of the health 
questionnaires, additional procedures that will take place at this Screening Visit include 
completing McGill Pain Questionnaire-Short form after the administration of a pain 
threshold and tolerance test called a Cold-Pressor Pain Sensitivity Test. The total time 
for the visit is approximately 2.5 hours. 
Health Questionnaires
At your Screening Visit, you will be asked to complete seven health questionnaires that 
will ask you about your pain level, pain tolerance, mental health, and social activities. 
These questionnaires will take approximately 20-30 minutes to complete. You will be 
asked to repeat these same questionnaires in recovery with your surgeon, and  during 
your 6-Week Follow-Up visit. 
Pain Scale
You will be verbally asked to rate your pain on a scale of 0 to 10, 0 being no pain, and 10 
being the most severe pain imaginable.  For this research, this will be done at the 
Screening Visit, while you are in the hospital (from the time you arrive in the PACU until 
72 hours after surgical wound closure), at your Post-Operative Visit (10-14 days after your 
surgery) with your surgeon, and at your 6-Week Follow-up Visit. 


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Medical Record
We will be looking into your electronic medical record for medical history and other 
information including the amount of narcotics and non-narcotic analgesics that were 
administered to you in the operative and postoperative period. This information will be 
recorded from the time you are in the operative room up until 72 hours after wound 
closure. 
Cold-Pressor Pain Sensitivity Test
Study doctors will work with you to determine your pain-medication doses, and you will 
be asked to come into the Aiken Medical Building thirty minutes before your pain 
medication dose is due. You will be asked to bring with you your upcoming dose of pain 
medication. Prior to taking your pain medication, you will then be administered a Cold-
Pressor Pain Sensitivity test. For this test, you will place your non-dominant hand in a 
bowl of ice water up to the wrist. Pain threshold is measured as the time in seconds that 
it takes for you to first report the sensation of pain in your hand that is in the ice water. 
Pain tolerance is measured by as the time in seconds that it takes for you to withdraw 
your hand from the ice water because it has become too uncomfortable for you to keep 
their hand in the ice water any longer. A cut-off of four minutes will be imposed to limit the 
potential for any tissue damage. At this time, you will be asked to remove your hand from 
the ice water, even if you feel that you could keep your hand in the ice water 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-Short form will be administered. 
After this questionnaire is complete, you will take the dose of opioid medication you 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-Short form will be administered again. 
You will be compensated $50 for this Screening Visit.
Surgical Visit 
On your day of surgery, you will be randomized to receive either ketamine or placebo during and 
after surgery for 24 hours. You cannot decide whether you will receive a ketamine or placebo for 
pain management. This will be randomly decided, like a lottery. There is a fifty-fifty chance of you 
being in either group.
If you agree to participate, you will be in one of the two groups;
Group #1 – “Ketamine” Group:
You will receive intravenous (IV) ketamine 15 minutes after induction of general anesthesia. 
Thereafter, a continuous IV drip of low dose ketamine will be run to conclude at 24 hours after the 
end of the surgery. The use of Ketamine will not change the type of anesthesia you get in the 
operating room. After the surgery, when you are in recovery, you will receive pain medications in 


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addition to the ketamine to help control your pain, and a Patient Controlled Analgesia (PCA) will 
be started for you, where you will be able to give yourself pain medicine as needed by the press 
of a button.                        
Group #2 – “Placebo” Group:
You will receive an intravenous infusion of normal saline (placebo) 15 minutes after induction of 
general anesthesia. Thereafter, a continuous IV drip of saline will be run to conclude at 24 hours 
after the end of the surgery. The use of this saline will not change the type of anesthesia you get 
in the operating room. After the surgery, when you are in recovery, you will receive pain 
medications in addition to the placebo to help control your pain, and a Patient Controlled 
Analgesia will be started for you, where you will be able to give yourself pain medicine as needed 
by the press of a button.
Each day, an Anesthesiologist or another member of the Acute Interventional Perioperative Pain 
Service (AIPPS), will visit you. They will ask you to rate your pain on a scale of 0-10. If your pain 
is not well-controlled, the AIPPS team are on call 24 hours a day to make adjustments to your 
care to ensure you are comfortable. The amount of pain medicine that you need will be part of 
the information collected for the research.
As is standard of care, pain will be monitored every four hours, except during the night when you 
are asleep. We will use a scale from 0-10, 0 being no pain, 5 being moderate pain and 10 being 
the worst imaginable pain. We will also ask you to score pain at its best and worst over the period 
since you were last asked. The amount of pain medication you use while in the hospital will also 
be collected. 
Ketamine is FDA approved for anesthesia. Ketamine has been approved and used for surgical 
and post-surgical pain management by UPMC since 2009; it is, however, not FDA approved for 
pain management.
Post-Operative Visit 
As is standard after this surgery, you will follow-up at Neurosurgery clinic at 10-14 days 
postoperatively. At this time you will be asked to complete the 6 health questionnaires again (Pain 
Medication review form, the Pain Catastrophizing Scale (PCS), the 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) and 
we will review your overall recovery and ask if you have had any complications since being 
discharged from the hospital. This visit will take approximately 1 hour. If for any reason, a visit in 
the clinic is not conducted during this time frame, you will be contacted by a study team member 
via phone to complete the above assessments. 
6-Week Follow-up Visit 
You will be asked to come to the Posner Pain Clinic in the Aiken Medical Building 
approximately 6-weeks after your surgery for a 6-Week Follow-Up Visit. The address for 
the Posner Pain Clinic is 532 South Aiken Avenue, Suite 407, Pittsburgh PA 15232. The 
procedures that will take place at this 6-Week Follow-Up Visit include completing a pain 
questionnaire after the administration of a pain threshold and tolerance test called a Cold-
Pressor Pain Sensitivity Test. The total time for the visit is approximately 1.5 hours.
Cold-Pressor Pain Sensitivity Test


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Study doctors will work with you to determine your pain-medication dose regimen, and 
you will be asked to come into the Aiken Medical Building thirty minutes before your pain 
medication dose is due. You will be asked to bring with you your upcoming dose of pain 
medication. Prior to taking their pain medication, you 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, the Pain Medication 
review form, the Pain Catastrophizing Scale (PCS), the 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. 
You will be compensated $50 for this 6-week follow-up visit. 
What are the possible risks, side effects, and discomforts of this research study?
You will be asked questions regarding your pain level, and you will also fill out health 
questionnaires for the study. This information will be considered protected health 
information and will be kept confidential per HIPAA privacy act. There is, however, a 
possibility of breach of confidentiality. That is, in very rare cases, people not associated 
with this research study may inadvertently see your identifiable research results. 
We will do everything in our power to prevent this from happening by keeping all research 
records in locked files, and identify medical information by a research record number, 
rather than by your name or social security number. The codebook file containing your 
name and number will be kept secure by the Study Team. 
There are risks and side effects of your surgery and anesthesia that your surgeon and 
anesthesiologist will discuss with you. These are separate from this study. You will be 
required to sign UPMC’s surgical consent form and anesthesia consent form in order to 
have your spine surgery. Again, these risks, side effects, and discomforts would still be 
present without participation in this study.
For your information, there are risks associated with medications and tests in this study. 
You can speak to your anesthesiologist about these if you want more information.
Risks of Ketamine
Infrequent Risks:
•
Blurred vision 
•
Confusion 
•
Drowsiness 
•
Increased or decreased blood pressure or heart rate 
•
Mental or mood changes 
•
Nausea and vomiting 
•
Dreams, hallucinations and delirium 
Rare Risks:


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•
Liver injury 
•
Allergic Reaction (rare)
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
If you are randomized to the ketamine group, you will receive ketamine infusion at the in-
patient units during your hospital stay. Should any complications associated with the 
medication occur, an emergency cart is readily available at the units. Acute Interventional 
Perioperative Pain Service (AIPPS), which is responsible for your postoperative pain 
management, is available 24/7 to address any associated issues.
Risks of completing questionnaires
•
Boredom
•
Frustration
•
Embarrassment
Risks of Cold-Pressor Test
Rare Risks:
•
Excessive painful sensation 
•
Tissue damage as a result of painful stimulation 
What are possible benefits from taking part in this study?
Subjects with chronic pain and opioid dependence may experience better analgesia in 
the postoperative period. 
What treatments or procedures are available if I decide not to take part in this 
research study?
Pain management plans for your surgery are available to you whether or not you 
participate in this study.  The anesthesiologist who will have direct care in your case will 
discuss alternative treatments for pain control with you.
If I agree to take part in this research study, will I be told of any new risks that 
may be found during the course of the study?


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You will be promptly notified if, during the conduct of this research study, any new 
information develops which may cause you to change your mind about continuing to 
participate.
Will my insurance provider or I be charged for the costs of any procedures performed as 
part of this research study?
You will not be billed for research procedures. 
Some of the services you will receive during this study are considered to be “routine 
clinical services” that you would have even if you were not in the study. These services 
will be billed to your health insurance company or you, if you do not have health insurance.
You will be responsible for paying any deductibles, co-payments or co-insurance that are 
a normal part of your health insurance plan. 
You may want to get more detailed information about what “routine clinical services” your 
health insurance is likely to pay for.  Talk to a member of the study staff and/or a UPMC 
financial counselor to get more information.  
Alternative treatments 
If you do not participate in this study, you will likely still receive a post-operative pain 
management plan that is standard of care at Presbyterian Hospital. 
Will I be paid if I take part in this research study?
You will be paid $50 upon completion of the Screening Visit  
You will be paid $50 upon completion of the 6-Week Follow-Up Visit 
Who will pay if I am injured as a result of taking part in this study?
University of Pittsburgh researchers and their associates who provide services at UPMC 
(UPMC) recognize the importance of your voluntary participation in their research studies.  
These individuals and their staffs will make reasonable efforts to minimize, control, and 
treat any injuries that may arise as a result of this research.  If you believe that you are 
injured as a result of the research procedures being performed, please contact 
immediately the Principal Investigator listed on the first page of this form. Emergency 
medical treatment for injuries solely and directly related to your participation in this 
research study will be provided to you by the hospitals of UPMC.  It is possible that UPMC 
may bill your insurance provider for the costs of this emergency treatment, but none of 
these costs will be charged directly to you.  If your research-related injury requires medical 
care beyond this emergency treatment, you will be responsible for the costs of this follow-
up care unless otherwise specifically stated below.  There is no plan for monetary 
compensation. You do not, however, waive any legal rights by signing this form.
Who will know about my participation in this research study?
Any information about you obtained from this research will be kept as confidential (private) 
as possible.  All records related to your involvement in this research study will be stored 
in a locked file cabinet. Your identity on these records will be indicated by a case number 
rather than by your name, and the information linking these case numbers with your 
identity will be kept separate from the research records.  You will not be identified by 


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name in any publication of the research results.  We will attempt to preserve your medical 
record and participation in this study as confidentially as possible, but breach of 
confidentiality is a risk of participation. 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.
Will this research study involve the use or disclosure of my identifiable medical 
information?
This research study will involve the recording of past, current and/or future identifiable 
(pertaining to only you) medical information from your hospital and/or other health care 
provider (e.g. physician office) records.  This information that will be recorded will be 
limited to diagnostic information, lab results, medications, and medical history.  The 
information will be used to determine your eligibility for this study and to follow your care 
once you are enrolled in the study.
This research study will result in identifiable information that will be placed into your 
medical records held at UPMC facilities. The nature of the identifiable information 
resulting from your participation in this research study that will be recorded in your medical 
record includes response to study treatment including adverse events (side effects).
Who will have access to identifiable information related to my participation in this 
research study?
In addition to the investigators listed on the first page of this authorization (consent) form 
and their research staff, the following individuals will or may have access to identifiable 
information (which may include your identifiable medical information) related to your 
participation in this research study: 
Authorized representatives of the University of Pittsburgh Research Conduct and 
Compliance Office may review your identifiable research information (which may 
include your identifiable medical information) for the purpose of monitoring the 
appropriate conduct of this research study. 
Authorized representatives of the study team, who are also part of the Department 
of Anesthesiology and the Acute Interventional Perioperative Pain Service, will 
review and/or obtain identifiable information (which may include your identifiable 
medical information) related to your participation in this research study for the 
purpose of monitoring the accuracy and completeness of the research data and 
for performing required scientific analyses of the research data. 
Authorized representatives of the UPMC hospitals or other affiliated health care 
providers may have access to identifiable information (which may include your 
identifiable medical information) related to your participation in this research study 
for the purpose of (1) fulfilling orders, made by the investigators, for hospital and 
health care services (e.g., laboratory tests, diagnostic procedures) associated with 
research study participation; (2) addressing correct payment for tests and 
procedures ordered by the investigators; and/or (3) for internal hospital operations 
(i.e. quality assurance).


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In unusual cases, the investigators may be required to release identifiable 
information (which may include your identifiable medical information) related to 
your participation in this research study in response to an order from a court of law.  
If the investigators learn that you or someone with whom you are involved is in 
serious danger or potential harm, they will need to inform, as required by 
Pennsylvania law, the appropriate agencies.
Authorized representatives of the U.S Food and Drug Administration (FDA) and 
other regulatory agencies may review and/or obtain your identifiable information 
(which may include your identifiable medical record information) related to your 
participation in this research study for the purpose of monitoring the accuracy of 
the research data
For how long will the investigators be permitted to use and disclose identifiable 
information related to my participation in this research study?
The investigators may continue to use and disclose, for the purposes described above, 
identifiable information (which may include your identifiable medical information) related 
to your participation in this research study for an indefinite period of time. Your research 
information may be shared with investigators conducting other research.  This information 
may be identifiable. 
Per University of Pittsburgh policy all research records must be maintained for at least 7 
years following final reporting or publication of a project.
May I have access to my medical information that results from my participation in 
this research study?
In accordance with the UPMC Notices of Privacy Practices document that you have been 
provided, you are permitted access to information (including information resulting from 
your participation in this research study) contained within your medical records filed with 
your health care provider.
A description of this clinical trial will be available on http://www.clinicaltrials.gov, as 
required by US Law.  This website will not include information that can identify you.  At 
most, the website will include a summary of the results.  You can search this website at 
any time.
There is no plan to share study results with participants at this time. 
Is my participation in this research study voluntary?
Your participation in this research study is completely voluntary. Whether or not you 
provide your consent for participation in this research study will have no effect on your 
current or future relationship with the University of Pittsburgh.  Whether or not you provide 
your consent for participation in this research study will have no effect on your current or 
future medical care at a UPMC hospital or affiliated health care provider or your current 
or future relationship with a health care insurance provider.
Your anesthesiologist is involved as an investigator in this research study.  As both your 
doctor and a research investigator, s/he is interested both in your medical care and the 


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conduct of this research study.  Before agreeing to participate in this research study, or 
at any time during your study participation, you may discuss your care with another doctor 
who is not associated with this research study.  You are not under any obligation to 
participate in any research study offered by your anesthesiologist.
May I withdraw, at a future date, my consent for participation in this research 
study?
You may withdraw, at any time, your consent for participation in this research study. Any 
identifiable research or medical information recorded for, or resulting from, your 
participation in this research study prior to the date that you formally withdrew your 
consent may continue to be used and disclosed by the investigators for the purposes 
described above. 
To formally withdraw your consent for participation in this research study you should 
provide a written and dated notice of this decision to the principal investigator of this 
research study at the address listed on the first page of this form.
Your decision to withdraw your consent for participation in this research study will have 
no effect on your current or future relationship with the University of Pittsburgh.  Your 
decision to withdraw your consent for participation in this research study will have no 
effect on your current or future medical care at a UPMC hospital or affiliated health care 
provider or your current or future relationship with a health care insurance provider.
If you decide to withdraw from study participation after you have received the study drug, 
no study assessments will be done after your withdrawal.
Rights to revoke authorization/how to revoke
You can always withdraw your authorization to allow the research team to review your 
medical records by contacting the investigator listed on the first page and making the 
request in writing. 
Implications of revocation of authorization
If you do so, you will no longer be permitted to participate in this study. Any information 
obtained from you up to that point will continue to be used by the research team
If I agree to take part in this research study, can I be removed from the study 
without my consent?
It is possible that you may be removed from the research study by the researchers if, for 
example, you have an unexpected change, complication in your anesthesia or surgery or 
serious adverse reaction. If you are withdrawn from participation in this research study, 
you will still be treated for your post-surgical pain. Please consult your surgeon or 
anesthesiologist if you have any further concerns. 


University of Pittsburgh MODCR19020144-017    Effective: 1/4/2022    Expires: 1/3/2023
                                                                          Page 11 of 12                                          
****************************************************************************************************
**********************
VOLUNTARY CONSENT
The above information has been explained to me and all of my current questions have 
been answered. I understand that I am encouraged to ask questions about any aspect of 
this research study during the course of this study, and that such future questions will be 
answered by a qualified individual or by the principal investigator listed on the first page 
of this consent document at the telephone number given. I understand that I may always 
request that my questions, concerns or complaints be addressed by a listed investigator.  
I understand that I may contact the Human Subjects Protection Advocate of the IRB 
Office, University of Pittsburgh (1-866-212-2668) to discuss problems, concerns, and 
questions; obtain information; offer input; or discuss situations in the event that the 
research team is unavailable.  
By signing this form, I agree to participate in this research study and to authorize Dr. 
Chelly and the members of his research team to access my medical records and extract 
research data from them, as described in this document. Dr. Jacques Chelly will sign this 
consent and a copy of this consent form will be given to me. Also, I further certify that no 
research component of this protocol was begun until after the consent form was signed.
____________________________________
            
Participant’s Signature
 ____________________________________
____________
Printed Name of Participant
Date
CERTIFICATION of INFORMED CONSENT
I certify that I have explained the nature and purpose of this research study to the above-
named individual(s), and I have discussed the potential benefits and possible risks of 
study participation. Any questions the individual(s) have about this study have been 
answered, and we will always be available to address future questions as they arise.  I 
further certify that no research component of this protocol was begun until after this 
consent form was signed.
___________________________________
________________________
Printed Name of Person Obtaining Consent
Role in Research Study


University of Pittsburgh MODCR19020144-017    Effective: 1/4/2022    Expires: 1/3/2023
                                                                          Page 12 of 12                                          
__________________________________
____________
Signature of Person Obtaining Consent
Date 

Prot_000.pdf: 
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: 


 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
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 
Statistical Analysis Plan – Approved 09/03/2019 
 
 


 
 
 
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.