Clinical trial NCT05477875
Conditions: Photorefractive Keratectomy Myopia Hyperopia
Sponsor: University of Florida
Start date: 2024-02-01; Completion date: 2025-01-22
Enrollment: 35 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Photorefractive Keratectomy (PRK) is a commonly performed corneal refractive surgery but has significant post-operative pain. Pain medications after PRK are typically opioid-acetaminophen combinations. Alternatives to opioid medication are worth consideration. Patients will receive PRK in each eye sequentially, using the cannabinoid or codeine/acetaminophen for one eye and the other treatment for the fellow eye two weeks later.

Detailed description:

Arms: arm 1: Oral cannabinoid arm 2: Oral codeine-acetaminophen for controlling pain
Interventions: intervention 1: oral cannabinoid intervention 2: oral codeine/acetaminophen
Intervention descriptions: intervention 1: dronabinol intervention 2: 10 tablets of acetaminophen-codeine combination (300-30mg) without refills.

Protocol documents:
ICF_002.pdf: 
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INFORMED CONSENT FORM 
to Participate in Research, and 
AUTHORIZATION 
to Collect, Use, and Disclose Protected Health Information (PHI) 
 
INTRODUCTION 
 
Name of person seeking your consent:  
 
 
 
 
 
 
 
 
 
Place of employment & position: 
 
 
 
 
 
 
 
 
 
 
 
GENERAL INFORMATION ABOUT THIS STUDY 
 
1. Name of Participant ("Study Subject") 
 
___________________________________________________________________ 
 
 
 
 
2. What is the title of this research study (this “Research Study”)? 
 
Randomized, Controlled Cross-over Comparison of Oral Cannabidiol to Oral Opioid for Postoperative 
Photorefractive Keratectomy Pain Control 
 
3. Whom do you call if you have questions about this Research Study (the “Study Team”)? 
 
Principal Investigator: Walter A. Steigleman, M.D. - (352) 265-2020 
Research Coordinator:  
Coinvestigator: Sonal S. Tuli, M.D.- (352) 265-2020 
Coinvestigator: Yujia Zhou, M.D. (352) 265-2020 
 
4. Who is paying for this Research Study? 
 
The sponsor of this study is the Consortium for Medical Marijuana Clinical Outcomes Research. 
 
5. In general, what do you need to know about this Research Study? 
 
Agreeing to become involved in any research is always voluntary. By signing this form, you are not 
waiving any of your legal rights. If you decide not to participate in this research, you will not be 
penalized in any way and you will not lose any benefits to which you are entitled. If you have questions 
about your rights as a research subject, please call the University of Florida Institutional Review Board 
(IRB) office at (352) 273-9600.  
 


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A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you.  At most, the Web site will include 
a summary of the results. You can search this Web site at any time.  
a) In general, what is the purpose of the research? How long will you be involved?  
 
We will compare the safety and efficacy of oral cannabidiol (CBD) to oral codeine-acetaminophen for 
controlling pain after photorefractive keratectomy (PRK). PRK is a commonly performed corneal 
refractive surgery used to correct refractive errors, similar to laser-in-situ keratomileusis (LASIK). If you 
participate in this study, you will first be evaluated in the clinic to find out if the PRK procedure might 
work for you. If you are eligible, you will undergo PRK in one eye, then the other eye two weeks later. 
You will also take surveys and return for postoperative clinic visits most likely for about 3 months after 
your surgery. This study therefore usually involves participation for about 4 months. Some patients with 
thicker glasses before surgery may take longer to stabilize and may need to be followed for up to 6 
months after surgery.  
 
b) What is involved with your participation, and what are the procedures to be followed in the 
research?  
 
Participation involves several clinic visits, PRK surgery in each eye, 1 at a time separated by 2 weeks, 
taking the prescribed narcotic pain medication or CBD, and completing surveys on your symptoms for up 
to four months. The first visit is a routine refractive surgery consultation, not part of the research study, 
where your eligibility and measurements for PRK will be evaluated. After this, you will schedule two PRK 
surgeries, one for each eye, separated by two weeks. After each surgery, you will receive standard 
postoperative treatment for PRK including bandage contact lens, artificial tears, medicated eyedrops 
(steroid, non-steroidal anti-inflammatory drug, and antibiotic), oral Ibuprofen, and either codeine-
acetaminophen or CBD.  
 
Since we are trying to find out which pain-relieving medicine might be better, you will receive a different 
pain medicine after each eye surgery.  The order of pain medications will be randomized, much like the 
flip of a coin. Some subjects will receive CBD after the first eye surgery and then the 
codeine/acetaminophen after the second eye and other patients the order of medications will be 
reversed. All subjects will receive either of the 2 pain medications after each eye surgery. There is no 
placebo group for this study. For each eye, you will then return to the clinic for postoperative evaluation 
for up to 6 months after the second eye’s surgery and complete surveys about your vision, experience, 
and pain level. You will be expected to take the prescribed medications as instructed to the best of your 
ability and report any missed medications to the principal investigator. 
 
c) What are the likely risks or discomforts to you?  
 
PRK is a refractive surgery, which includes several known risks and discomforts related to the surgery 
itself. For PRK not part of a study, some patients report experiencing pain, anxiety, and discomfort 
during the surgery, although most patients tolerate the surgery well. In the week after surgery, eye 
irritation, dry eye, eye pain, blurry vision, glare, visual halos, and light sensitivity are common. 
Complications such as bruising, corneal scarring, infection, bleeding, loss of vision, double vision, and 
severe dry eye are rare but possible. You may also experience constipation, stomach upset, nausea, 


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dizziness, allergic reaction, and loss of appetite because of some of the routine medications used after 
PRK.  
 
Specific to this study, there is no expected increased risks of surgical complications as mentioned above. 
One significant difference of this study is that routine PRK now usually involves treating both eyes at the 
same time on the same day whereas during this study, one eye will be treated on one day and the other 
eye treated 2 weeks later. Some of the discomforts of PRK surgery may be experienced twice by patients 
participating in this study. For some patients with strong glasses prescriptions before surgery, they may 
experience difficulties with vision and depth perception as the eyes may not work well together in the 2 
weeks between surgeries. By enrolling in this study, you will experience more clinic visits, recovery time, 
and surveys than if you had undergone PRK outside of this study.  
 
One of the medications used for postoperative pain in this study is CBD. CBD is not federally approved to 
treat this condition. Some side effects patients report when using CBD are sleepiness, decreased 
appetite, diarrhea, liver enzyme elevations, fatigue, malaise, rash, insomnia, sleep problems and 
infections. CBD may cause sleepiness impairing the ability to safely drive or operate machinery. Patients 
should not drive or operate machinery until they understand the effect CBD has on their function.  
 
Use of CBD may result in a positive drug test for marijuana or THC for about a month after taking it. So, 
you need to wait at least 30 days after the last dose of CBD before taking a drug test for a job or other 
reasons.  
 
Another medication used in this study is ibuprofen which is in the family of non-steroidal anti-
inflammatory drugs (NSAIDs). NSAIDs such as ibuprofen, cause an increased risk of serious 
gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the 
stomach or intestines, which can be fatal. These events can occur at any time during use and 
without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer 
disease and/or GI bleeding are at greater risk for serious GI events. NSAIDs such as ibuprofen, 
cause an increased risk of serious cardiovascular thrombotic events, including myocardial 
infarction and stroke, which can be fatal. This risk may occur early in the treatment and may 
increase with duration of use. 
 
The codeine/acetaminophen pain medication, also known as Tyelnol #3, contains an opioid 
medication with a risk of misuse, abuse, and addiction. The period of use in the study is only for 
up to 5 days, and therefore, the risk of it becoming habit-forming is likely lower than that of 
opioids used for a longer duration. Patients with a personal history of misuse, abuse, and 
addiction to opioids or prefer to not take any opioids should not participate in this study.  
 
d) What are the likely benefits to you or to others from the research? 
 
There may be no direct benefit to you.  By participating in this study, you will receive PRK surgery at no 
cost to you, which costs an estimated $4000 for both eyes. The results from this study will also help 
other ophthalmologists determine whether CBD is an effective treatment for pain and discomfort after 
PRK. Current evidence demonstrates that opioid use is associated with some unpleasant side-effects and 
that legitimate opioid prescriptions may result in future use. This study may demonstrate that CBD is a 
safe, effective alternative to opioid medication. 
 


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e) What are the appropriate alternative procedures or courses of treatment, if any, that might be 
helpful to you?  
 
PRK services are available outside of this study if you decide not to enroll. Non-surgical alternatives 
include refractive prescriptions for glasses or contact lenses. LASIK or other forms of refractive surgery 
are also options not included within this study. Some patients may be eligible for cataract surgery 
instead of refractive surgery. 
 
 
Additional and more detailed information is provided within the remainder of this Informed Consent 
form. Please read before deciding if you wish to participate in this study. 
 
WHAT CAN YOU EXPECT IF YOU PARTICIPATE IN THIS STUDY? 
 
6. What will be done as part of your normal clinical care (even if you did not participate in this 
Research Study)?  
 
If you are seeking refractive surgery, you will be evaluated and informed of all surgical and nonsurgical 
options (see section 5e above) regardless of your participation in this study. Your doctor will do several 
tests on your eyes to determine your visual acuity, eye pressure, and eye health during your initial visit 
and evaluate your eligibility for each of these surgical and nonsurgical options. If you are eligible for PRK 
and elect to undergo the surgery, you will be counseled on the risks and benefits before scheduling 
surgery. 
 
PRK takes a few minutes for each eye, and you will be given local or topical anesthetic eyedrops. During 
surgery, an eyelid holder will be placed on the eye to prevent blinking. Your surgeon will remove the 
surface tissue of your cornea using a brush, laser, alcohol solution, or specialized blade. A laser 
programmed with your eye measurements will reshape your cornea, and you may smell and hear this 
process. Your vision will be blurry, and you will not be able to see the surgery. Afterwards, you will 
receive a protective contact lens, medicated eyedrops, and pain medication to take after surgery. Your 
doctor will see you again in the days, weeks, and months after surgery to ensure that you are healing 
well and adjust your treatment to best improve your vision.  
 
7. What will be done only because you are in this Research Study?  
 
If you participate in this study, you will have two separate surgeries separated by 2 weeks, instead of 
both eyes at once, and you will also take surveys in addition to your normal care. Once you decide to 
participate in the study, the first eye surgery will be scheduled. This will require a 1 week follow up visit. 
Then, 2 weeks after the first eye surgery, the second eye will have surgery. The second eye surgery will 
also have a 1 week follow up visit. Each surgery will also have a 1 month follow up visit. So, after 
enrolling in the study, each eye will have a surgery day and a 1 week and 1 month follow up. This is 6 
total visits in less than 2 months. There will likely be increased time spent during each visit of at least 30 
minutes for additional testing and completing surveys because of your participation in the study. 
 
 If you had PRK not as part of this study, you would have both eyes treated on the same day and only 
have a single 1 week and 1 month visit and would not necessarily complete additional testing or surveys.  
 


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The PRK procedure and routine postoperative medications (eye drops) are the standard for patients 
having PRK not part of this study. The main differences from routine PRK for this study is that each eye 
will be treated separately 2 weeks apart and that for 1 of the eye surgeries, the medication used for pain 
control will be CBD, which is not currently FDA approved for treating pain.  
 
Your surgery costs will also be waived if you participate in this study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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An example of the surveys is below:  
 
 
 


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It is possible that your research information with all personally identifiable information removed, could 
be used for future research studies or distributed to another investigator for future research studies 
without additional informed consent from you or your legally authorized representative.  
 
If any identifiable information was collected as part of this research, it is possible that your research 
information, with all personally identifiable information removed, could be used for future research 
studies or distributed to another investigator for future research studies without additional informed 
consent from you or your legally authorized representative.  
 
If you have any questions now or at any time during this Research Study, please contact one of the 
Research Team members listed in question 3 of this form. 
 
 
8. What identifiable health information will be collected about you and how will it be used? 
 
 
The Research Team will collect demographic information, results of physical exams, medical history, eye 
measurements, surgical details, and surveys for the purpose of evaluating your eligibility for this study 
and for statistical analysis. 
 
The Research Team may collect this information from other healthcare providers, such as laboratories, 
which are a part of this research, as well as healthcare providers that are not part of this research (other 
doctors, hospitals or clinics). Other professionals at the University of Florida or Shands Hospital who 
provide study-related care, and the University of Florida Institutional Review Board (IRB), may also 
collect your health information.  
 
The Research Team listed in question 3 above will use or share your health information as described 
below to carry out this research study.  
 
9. With whom will this health information be shared? 
 
This health information may be shared with: 
• 
The Consortium for Medical Marijuana Clinical Outcomes Research (study sponsor) 
• 
United States governmental agencies which are responsible for overseeing research, such as the 
Food and Drug Administration, the Department of Health and Human Services, and the Office of 
Human Research Protections 
 
• 
Government agencies which are responsible for overseeing public health concerns, such as the 
Centers for Disease Control and federal, state and local health departments 
• 
The IRB that reviewed this Research Study and ensures your rights as a study subject are 
protected 
 
Otherwise, your identifiable health information will not be shared without your permission unless 
required by law or a court order. Once your health information is shared with those listed above, it is 
possible that they could share it without your permission because it would no longer be protected by 
the federal privacy law.  


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10. How long will you be in this Research Study? 
 
You will be part of this research study for up to 6 months. This includes the time from your initial surgery 
to your last postoperative visit and usually for 3 months after your second surgery. Some patients with 
thicker glasses before surgery may need additional time for vision to stabilize. Such patients will be 
examined in clinic visits for up to 6 months to monitor this process.  
 
This Authorization to use and share your health information expires at the end of the study, unless you 
revoke it (take it back) sooner. 
 
11. How many people are expected to take part in this Research Study? 
 
Thirty-five people are expected to take part in this research study. 
 
WHAT ARE THE RISKS AND BENEFITS OF THIS STUDY AND WHAT ARE YOUR OPTIONS? 
 
12. What are the possible discomforts and risks from taking part in this Research Study? 
 
During PRK surgery which is part or is not part of this research study patients may experience pain, 
anxiety, and discomfort during the surgery. In the week after surgery, eye irritation, dry eye, eye pain, 
blurry vision, glare, visual halos, and light sensitivity are common. Complications such as bruising, 
corneal scarring, infection, bleeding, loss of vision, double vision, and severe dry eye are rare and 
possible after PRK surgery with or without participation in the research study. You may also experience 
constipation, stomach upset, nausea, dizziness, allergic reaction, and loss of appetite because of some of 
the routine or study medications. Some patients may still require glasses or retreatment after surgery. 
Each of these risks is true for PRK surgery with or without participation in the research study. 
 
The CBD oral solution used in this research study is not federally approved to treat this condition, 
although this substance is generally recognized as safe for certain individuals. It is possible that it’s use 
may result in a positive drug screen for marijuana. If you have a work or other social situation where a 
positive drug screen may cause a problem, you should not participate in the study. If you are pregnant 
or considering pregnancy, you should not participate in the study. 
 
By enrolling in this study, you will undergo PRK for each eye on separate days about 2 weeks apart and 
experience more clinic visits and surveys than if you had undergone PRK outside of this study. 
 
This Research Study may also include risks that are unknown at this time. 
 
Please note, participating in more than one research study or project may further increase the risks to 
you. If you are already enrolled in a research study, please inform one of the Research Team members 
listed in question 3 of this form or the person reviewing this consent with you before enrolling in this or 
any other research study or project. 
 
During the study, the Research Team will notify you of new information that may become available and 
might affect your decision to remain in the study.  
 


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The University of Florida is required by law to protect your health information. Your health information 
will be stored in locked filing cabinets or on computer servers with secure passwords, or encrypted 
electronic storage devices, as required by University policy. However, there is a slight risk that 
information about you could be released inappropriately or accidentally. Depending on the type of 
information, a release could upset or embarrass you, or possibly affect your ability to get insurance or a 
job.  
 
If you wish to discuss the information above or any discomforts you may experience, please ask 
questions now or call one of the Research Team members listed in question 3 in this form. 
 
13a. What are the potential benefits to you for taking part in this Research Study? 
 
 
You may or may not benefit from participating in this study. The potential benefit is that the CBD will 
provide effective pain relief in place of opioids, which can possibly result in their future use. 
 
13b. How could others possibly benefit from this Research Study? 
 
The findings from this study will also help other ophthalmologists determine whether CBD is an effective 
treatment for pain and discomfort after PRK. Current evidence demonstrates that opioid use is 
associated with unfavorable side-effects and that legitimate opioid prescriptions fuel the opioid 
addiction crisis. This study may demonstrate that CBD is safe, effective alternative to opioid medication 
for other patients. 
 
13c. How could the Research Team members benefit from this Research Study? 
 
In general, presenting research results helps the career of a researcher. Therefore, the Research Team 
listed in question 3 of this form may benefit if the results of this Research Study are presented at 
scientific meetings or in scientific journals. 
 
14. What other choices do you have if you do not want to be in this study?  
 
If you do not want to be in this study, you have the option to pursue surgical and nonsurgical treatments 
for refractive errors. These options include refractive prescription for glasses, other refractive surgeries 
such as LASIK, or cataract surgery. You also have the option of pursuing PRK surgery without enrolling in 
this study for a commercial fee estimated around $4000. 
 
You may also refuse to authorize the use of your health information, but if you refuse, you may not be 
allowed to be in this research study or receive any research-related treatment that is only available in 
this research study. However, your decision not to sign this Authorization will not affect any other 
treatment you may be eligible to receive. 
 
15a. Can you withdraw from this study? 
 
You may withdraw your consent and stop participating in this Research Study at any time. If you do 
withdraw your consent, there will be no penalty to you, and you will not lose any benefits to which you 
are otherwise entitled. If you decide to withdraw your consent to participate in this Research Study for 


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any reason, please contact the Research Team listed in question 3 of this form. They will tell you how to 
safely stop your participation. 
 
You can also change your mind and take back this Authorization at any time by sending a written notice 
to the Research Team listed in question 3 of this form to let them know your decision. If you take back 
this Authorization, the Research Team may only use and disclose your health information already 
collected for this research study. No additional health information about you will be collected or 
disclosed to the Research Team. However, if you take back this Authorization, you may not be able to 
continue in this study. Please discuss this with a member of the Research Team listed in question #3. 
 
15b. Can the Principal Investigator withdraw you from this Research Study?  
 
You may be withdrawn from this Research Study without your consent for the following reasons: 
 
You are unable to complete any/all portions of the study protocol including medication use, follow up 
visits and patient reported outcomes tools.  
 
WHAT ARE THE FINANCIAL ISSUES IF YOU PARTICIPATE? 
 
16. If you choose to take part in this Research Study, will it cost you anything? 
 
No. There will be no extra cost to you for participating in this Research Study. 
 
 
17. Will you be paid for taking part in this Research Study? 
 
You will not be paid for taking part in this research study. Only the cost of surgery and study-related 
medications will be waived. 
 
18. What if you are injured while in this Research Study? 
  
If you are injured as a direct result of your participation in this study, only the professional services that 
you receive from any University of Florida Health Science Center healthcare provider will be provided 
without charge.  These healthcare providers include physicians, physician assistants, nurse practitioners, 
dentists or psychologists. Any other expenses, including Shands hospital expenses, will be billed to you 
or your insurance provider.  
 
You will be responsible for any deductible, co-insurance, or co-payments. Some insurance companies 
may not cover costs associated with research studies or research-related injuries. Please contact your 
insurance company for additional information.  
 
The Principal Investigator will determine whether your injury is related to your participation in this 
study.  
 
No additional compensation is routinely offered. The Principal Investigator and others involved in this 
study may be University of Florida employees. As employees of the University, they are protected under 
state law, which limits financial recovery for negligence. 


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Please contact the Principal Investigator listed in question 3 of this form if you experience an injury or 
have questions about any discomforts that you experience while participating in this study. 
SIGNATURES 
 
As an investigator or the investigator’s representative, I have explained to the participant the purpose, 
the procedures, the possible benefits, and the risks of this Research Study; the alternative to being in 
the study; and how the participant’s protected health information will be collected, used, and shared 
with others:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Person Obtaining Consent and Authorization 
 
 
Date 
 
You have been informed about this study’s purpose, procedures, possible benefits, and risks; the 
alternatives to being in the study; and how your protected health information will be collected, used 
and shared with others. You have received a copy of this form. You have been given the opportunity to 
ask questions before you sign, and you have been told that you can ask questions at any time.  
 
You voluntarily agree to participate in this study. You hereby authorize the collection, use and sharing of 
your protected health information as described above. By signing this form, you are not waiving any of 
your legal rights. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Person Consenting and Authorizing  
 
 
 
Date 
 

Prot_000.pdf: 
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zProtocol 
1. Project Title 
Randomized, Controlled Cross-over Comparison of Cannabidiol to Oral Opioid for 
Postoperative Photorefractive Keratectomy Pain Control 
2. Investigator(s): 
W. Allan Steigleman, M.D. 
Sonal Tuli, M.D. 
Yujia Zhou, M.D.  
3. Abstract: 
Photorefractive Keratectomy (PRK) is a commonly performed corneal refractive surgery 
for the correction of refractive errors. The procedure is less popular than Laser In-Situ 
Keratomileusis (LASIK) due to increased post-operative pain and discomfort associated with 
PRK, but some patients and surgeons increasingly prefer PRK for its superior safety profile in 
select patients.  
Surgeons prescribe topical and oral medications to promote healing and reduce post-
operative discomfort after PRK, with additional topical anesthetics and/or oral narcotics for 
break-through pain. Oral narcotic agents are typically opioid-acetaminophen combinations. 
Current evidence, however, demonstrates that opioid use is associated with unfavorable side-
effects and that legitimate opioid prescriptions have fueled the current opioid addiction crisis. A 
safe, effective means of post-operative pain ibcontrol is needed, and alternatives to opioid 
medication are worth consideration. 
We propose a crossover randomized paired-eye controlled trial to compare post-PRK 
pain control with a CBD chemovar to codeine/acetaminophen. Patients will receive PRK in each 
eye sequentially, using the CBD chemovar or codeine/acetaminophen for one eye and the other 
treatment for the fellow eye two weeks later. This crossover paired-eye design allows for robust 
self-control. Masking treatments will not be possible given the different appearance and dosing 
regimen of treatments. Surgical and post-operative parameters will be standardized between 
the two arms. 
Medication use, pain levels and potential side effects will be collected. Primary outcome 
measures will be change from baseline in daily pain intensity on the pain rating scale to 
postoperative day 4 and responses between the study medication and the 
opioid/acetaminophen combination medication. Secondary measures will be surgical, refractive 
error, and patient reported outcomes noted at 1 and 3 months postoperatively. Final refractive 
error determinations will not be determined until 6 months postoperatively for patients having 
greater than 6D of myopia preoperatively.  
 


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4.  Background: 
Photorefractive keratectomy (PRK) is a common corneal refractive surgery with a 
superior safety profile compared to Laser In-Situ Keratomileusis (LASIK) for some patients but 
has increased post-operative pain and discomfort, frequently requiring opioids for post-operative 
pain control. Published evidence suggests that hemp-based cannabidiols (CBD) may be a 
suitable pain-control alternative, and we propose this study to evaluate the efficacy and safety of 
oral CBD for reduction of PRK post-operative pain compared to opioid-acetaminophen 
combinations. 
PRK is a commonly performed corneal refractive surgery for the correction of myopia, 
hyperopia and astigmatism. The procedure is not as popular as LASIK due to the increase in 
post-operative pain and discomfort associated with PRK.1-4 Many patients and surgeons choose 
PRK for a perceived enhanced safety profile over LASIK. PRK has recently gained popularity 
with some surgeons as a safer procedure than LASIK in select patients with predisposing 
conditions which may lead to increased post-operative complications such as dry eye, ectasia, 
and flap dislocation. A safe, effective means of post-operative pain control is needed.  
Refractive surgeons employ a host of topical and oral medications to promote healing 
and to reduce post-operative discomfort after PRK. Topical antibiotics, non-steroidal, steroidal 
anti-inflammatory and rewetting drops are typically used. Oral non-steroidal medications are 
employed for pain control in a fraction of patients as well.5,6 For break-through pain, patients are 
often prescribed topical anesthetics and/or oral narcotics.  
Attempts to optimize the specific constituent components of this combination approach 
have been documented in the medical literature. Variability in efficacy and side effects with 
many components has been reported. Several types of bandage contact lens materials have 
been shown to offer varying rates of healing and patient post-operative comfort, with senofilcon 
A offering lowest pain reports.7-11 Topical nonsteroidal 12-23 and topical anesthetic 24-26 
medications have been demonstrated to be effective for pain control but offer the potential for 
delayed healing.27,28 Application of cold packs after surgery has been shown to reduce post-
PRK pain as well.29-33 Concerns for affected sensorium which can limit activities of daily living 
and the potential for abuse with narcotics has led some refractive surgeons instead to use oral 
gabapentinoids for post-operative pain management, but with limited success.34-37 
Combination approaches including a bandage contact lens, topical anesthetic, and 
topical nonsteroidal drops with oral narcotic medication for breakthrough pain has been shown 
to be more efficacious in addressing pain following PRK surgery.38-40 
Combination codeine/acetaminophen, hydrocodone/acetaminophen and 
oxycodone/acetaminophen are commonly used oral narcotic/analgesic combination medication 
for post-PRK pain.41 Use of transdermal fentanyl patches has been reported as well.42 Some 
evidence suggests codeine/acetaminophen may be better for post-PRK pain control than 
oxycodone containing combinations.43 However, opioid use has been associated with 
unfavorable side effects and social impacts. Unfavorable side effects including gastrointestinal 
and sensorium changes in patients taking a hydrocodone/acetaminophen combination have 
been reported.44-46 Current evidence suggests that legitimate opioid prescriptions for injury or 
surgery have fueled the current opioid addiction crisis.47, 48 The most common route for first 
exposure to opioids for persons who end up with opioid addiction is a legitimate prescription for 
an injury.49 Over 25% of select patient populations who were prescribed opioid medications for 


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acute pain have been reported to still be using them at one year.50 Alternative treatments are 
worth consideration.  
Published evidence suggests hemp-based cannabidiol (CBD) with or without 
tetrahydrocannabidiol (THC) may be a suitable post-surgical opioid pain control alternative.51, 52 
CBD products with lower THC content may be preferable to higher THC-containing products 
associated with impaired cognition. Additionally Capano et al. treated a series of 131 patients 
taking more than 50 daily baseline morphine equivalents with a low-THC oral CBD chemical 
variant and found 53.2% of patients were able to reduce opioid medication use and had 
improved quality of life measures.53 Laboratory data also indicate that topically applied CBD can 
reduce nociceptive pain responses in a superficial ocular injury model suggesting CBD sensitive 
pain-regulatory pathways in the cornea.54 If the selected chemovar is clinically helpful for 
patients otherwise requiring an average of 50 morphine equivalents daily, we expect the 
intervention to be effective in our patient population typically well-managed with up to 18 
morphine equivalents per day.  
A paucity of data exists evaluating the efficacy of alternative anxiolytic and pain modulating 
treatments including CBD containing products to control post-PRK pain. Based on 
demonstrated success in other pain control applications as well as evidence of CBD sensitive 
corneal pathways, we postulate that CBD treatment perioperatively may be a suitable method 
for post-PRK pain control. An alternative low-THC CBD-based agent, if found to be effective for 
pain control, could decrease potential for opioid abuse, opioid-related complications and 
inherently decrease administrative burden for both prescribing and dispensing post-operative 
medications.  
 
5. Specific Aims: 
 
We will compare the safety and efficacy of a low-THC, oral CBD chemovar to oral 
codeine-acetaminophen for controlling post-operative PRK pain. 
 
6. Research Plan: 
 
Once a patient been evaluated, has been informed of the risks and benefits of the 
procedures, their cost and has decided on PRK, then the study will be introduced to the patient 
to determine their interest in participation. 
 
Up to fifty patients will be enrolled in the study with the goal of Thirty-five total patients 
completing the study and will include otherwise healthy patients with myopia meeting criteria 
for PRK without contraindications to any of the study medications. Patients will undergo PRK in 
each eye sequentially, separated by two weeks. Half of the patients will receive the CBD 
chemovar for pain control during the first surgery, and half will initially receive 
codeine/acetaminophen. Both arms will then cross over to the other pain-control treatment 
during the second surgery for the fellow eye two weeks later. 


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For the eye to be treated with the narcotic medication, patients will be prescribed 12 
tablets of codeine/acetaminophen (30mg/300mg) for break-through pain. Patients will be 
counseled that these medications may be taken as needed up to once every 4 hours (up to 18 
morphine equivalents daily), that use will preclude driving and, and that this medication may 
result in unfavorable side-effects including gastro-intestinal symptoms. Chemovars of CBD 
delivered via smoking and/or vaping were not considered for this study for the concern that 
eluted vapors may impede healing of the ocular surface. Sublingual tinctures were deemed to 
be potentially less reliable for precise dosing using a dropper, especially in subjects with 
impaired visual acuity in the immediate post-operative period. 
 
For the eye to be treated with the CBD chemovar, patients will be prescribed 20 CBD 
gummies (50mg) and instructed to use 2 of the chemovars (50mg total each dose) beginning 
the morning of the procedure and continuing twice daily through the evening dose on post-
operative day (POD) 4. The CBD chemovar selected for this study is a full spectrum CBD 
gummy provided by SunFlora which contains 50mg of CBD with less than 0.3% THC by weight. 
This product is readily available for direct consumer purchase without administrative 
encumbrances associated with higher level THC chemovars. The cannabinoid profile is verified 
by an independent laboratory using a host of chromatography techniques. The analysis includes 
screening for heavy metals, toxins, industrial chemicals, microbiological and pesticide 
contamination. CBD used for this study will all be selected from the same lot to reduce 
variability. A similar strength CBD product has been used in a published clinical study53 in 131 
patients without reported adverse events which should increase the likelihood of tolerability in 
our patient population. Some evidence suggests that as many as 10 million adults in the US 
consume supplement-grade CBD products daily with limited adverse effects reported.54 Patients 
will be counseled that use of this product will preclude driving until they experience how the 
product affects them, and that this medication may result in unfavorable side-effects including 
sleepiness, decreased appetite, diarrhea, liver enzyme elevations, fatigue, malaise, rash, 
insomnia, sleep problems and infections. 
 
The investigators will pursue investigational new drug approval for this CBD chemovar 
prior to treating patients. 
Inclusion/exclusion criteria to ensure safety of study subjects: 
Inclusion criteria will be healthy adult patients except for myopia with suitable health for 
photorefractive keratectomy. 
Exclusion criteria will include pregnancy or lactating within the preceding 6 months of the 
procedure (female and male subjects will be counseled to practice acceptable methods of birth 
control until completing all study medications), concomitant use of amiodarone, isotretinoin, or 
sumatriptan. Female patients will be pregnancy tested on the day of each planned procedure. 
Other exclusion criteria include a history of poorly controlled diabetes, HIV (Human 
Immunodeﬁciency Virus) or other immune and collagen vascular disorders, glaucoma, herpetic 
eye disease (including simplex and Zoster), or corneal ectasia or dystrophy. Additional 
exclusion criteria include subjects with any history of seizure disorder, family history of seizure 
disorders, or head trauma, any history of liver disease or use of medications associated with 
liver dysfunction, any history of renal disease, or any history of cardiovascular disease, history 
of peptic ulcer disease, gastrointestinal hemorrhage and/or history of NSAID-related 
gastrointestinal adverse events. Subjects with a personal history of opioid misuse, abuse, or 
addiction will also be excluded from the study.  


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There is some evidence that prolonged, high dose CBD use (Epidiolex) has resulted in 
elevated transaminases. The fraction of patients experiencing CBD-associated liver injury in the 
literature are mostly children at 10mg/kg/day to 20mg/kg/day dosing with an equivalent total 
dose of 700 to 1400mg per day for a 70kg adult. Transaminase elevations have been reported 
in approximately 16% of patients after 90 days of use.56 This is the equivalent of 63,000mg 
cumulative dose for a 70kg adult. Approximately 2/3 of the patients with elevated transaminases 
were taking concomitant valproate.55 There is a very low likelihood of liver injury to adult 
subjects in this study taking 10 doses of 50mg of supplement-grade CBD for 500mg total 
exposure which is the equivalent of less than 1 day recommended dosing of Epidiolex. As listed 
above, any history of liver disease or use of medications associated with liver dysfunction is an 
exclusion criterion.  
Surgical and post-surgical procedures: 
 
All other surgical and post-operative parameters will be standardized between the two 
arms. All patients will undergo comprehensive medical history and eye exams including 
manifest and cycloplegic refractions, ocular dominance, wavefront analysis, corneal topography, 
corneal tomography, pachymetry, autorefraction, keratometry and iDesign aberrometry. 
Treatment plans with satisfactory quality infinity-calibrated iDesign profiles will be nomogram 
adjusted in minus cylinder by age as per center routine. After ensuring all manufacturer 
recommended laser daily calibrations have been completed, all surgeries will be performed by 
the same experienced surgeon (WAS). Epithelial debridement will be completed with an Amoil’s 
brush with a hyperopic head. Ablations will be performed with the VISX S4 (Johnson & 
Johnson) excimer laser using pupil tracking and iris registration when available. Patients will be 
coached to maintain fixation on the centration beam during ablations and recentering joystick 
maneuvers will be used as necessary to maximize pupil centration within the reticle overlay. 
Mitomycin C 0.02% will be applied in all cases for 20 seconds per 50 microns of ablation and 
irrigated with 15cc of room-temperature balanced salt solution. The mitomycin 0.02% sterile 
solution used in this protocol is supplied by Fagron Sterile Services (FDA Registered 503B 
Outsourcing Facility) NDC 71266-8475-03. The label indicates: Sterile Mitomycin Solution 
0.02% (0.2 mg per 1 mL preservative-free, single-dose syringe) Each mL contains: Mitomycin 
0.2 mg, Mannitol USP 0.4 mg, Water (HCl or NaOH for pH adjustment) For Ophthalmic Use 
Only (Not For IV Use) Storage: 2-8°C (36-46°F); Protect from Light 
 
 
Post-operatively, a senofilcon A bandage contact lens (Acuvue Oasys) will be used in the 
operative eye. Moxifloxacin 0.5%, ketorolac 0.5%, fluorometholone 0.1%, and preservative free 
rewetting drops, (Refresh Plus--carboxymethylcellulose sodium 0.5%) will be used in all patients 
4 times daily as per routine. Patients will be prescribed ibuprofen 800mg orally three times daily 
for constitutive use for the first 48 hours postoperatively to reduce pain and inflammation. All 
patients will be counseled to apply ice packs to their closed eyelids through a cloth or towel for 
approximately 15 minutes per hour while awake for the first 48 hours. Female patients of 
reproductive age will be given a pregnancy test prior to enrollment. 
 
Patients will be randomly assigned to either the oral CBD first or oral 
codeine/acetaminophen first treatment arms in a 1:1 ratio using a random number generator 
from Microsoft Excel. Patients will be assigned consecutive study identification numbers as they 
are enrolled. Identification numbers will be apportioned to each arm using the Excel 
randomization generator before the first patient is enrolled. Masking study patients from which 


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medication they are using will not be possible given the different appearance and dosing 
regimen of the two pain control agents. 
 
Patients will complete a pain diary to record pain levels on each POD starting on the 
evening of POD0 through re-evaluation and collection of data sheets on POD7. The diary will 
also contain subjective medication side effect descriptions and intensity. Patients will be 
provided with emergency contact information to contact the clinic and/or on-call personnel if 
they are concerned they are experiencing an adverse reaction to the procedure or one of the 
study medications. A medical review of symptoms will be performed at the follow up 
examination to assess the potential for adverse reactions to the procedure or any of the study 
medications. 
 
Opioid-based medication used by patients will be tabulated on the POD7 visit and 
unused medications will be disposed of in an RxDestroyer device in a witnessed fashion and 
witness forms will be entered into patients’ records in accordance with UF Health ambulatory 
clinic policies as specified in the Patient Supplied Controlled Substance Destruction and 
Recordkeeping Protocol.  
 
Patients will be given electronic versions of a Microsoft Forms survey tool to collect 
responses to selected questions from the Patient Reported Outcomes with LASIK (PROWL), 
NEI Refractive Error Quality of Life-42, Work Productivity and Activity Impairment and Ocular 
Surface Disease Index questionnaires. 
 
Safety Monitoring and Stopping Criteria: 
Baseline assessments will include a brief physical exam with vital signs and a thorough medical 
and psychiatric history, including a review of past medical history, concomitant medications, 
inclusion/exclusion criteria, and potential contraindications.  
PRK Study Schedule of Events
DATE
ITEM
NOTES
Presurgery
Preopoerative Assessment Potential Enrollment Date
1st Surgery 
Surgery of 1st Eye
Randomized to single pain medication
Postop Day 7
Postop Eval
Collection of diary, postoperative assessment of 1st surgery
2nd Surgery (2 
weeks after 1st)
Surgery of Fellow Eye
Other pain medication
Postop Day 7
Postop Eval
Collection of diary, postoperative assessment of 2nd surgery
1 Month 
Assessment 
Postop Eval
Weeks 3-5 after 1st surgery, evaluation for haze, outcomes 
assessment
3 Month 
Assessment
Postop Eval
Weeks 10-14 after 1st surgery, outcomes/complication 
assessment
6 month assessment Postop Eval
Weeks 24-28 after 1st surgery (only if >6D myopia preop)


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Follow-up visits will include monitoring for adverse events as listed above including 
reassessment of vital signs and review of patient symptom diaries. 
Subjects contacting the clinic and/or emergency on-call personnel between scheduled visits will 
be assessed via telephone for potential adverse events. If a potential adverse event is 
suspected, the subject will be recommended to stop the study medication and will be prescribed 
an alternative pain medication pro re nata.  
 
7. Possible Discomforts and Risks: 
 
Normal discomforts and risks associated with PRK for myopia may be experienced by 
patients. Patients will be receiving a pain medication for each of the surgical eyes. One pain 
medication is the acetaminophen/codeine product used for all PRK patients were Refractive 
Center standard protocol. The other eye will be treated with the CBD product. It is possible that 
subjects could experience less pain control with one or the other interventions. Based on clinical 
practice, most patients having bilateral surgery report more pain than those having single eye 
surgery. If a subject in this study has less pain control with one of the study agents, this pain level 
is likely to be lower than that experienced by routine patients having both eyes treated 
simultaneously.   
 
Other discomforts and risks are similar to those experienced by patients having PRK for 
myopia not involved in the research study. These can include intra-procedure anxiety and 
discomfort, post-operative pain, irritation, tearing, blurred vision, double vision, potential loss of 
vision and need for additional procedures.  
 
Study subjects will need to have each eye treated sequentially approximately 2 weeks 
apart. This will result in them having to convalesce twice from the procedure and attend additional 
clinic visits than if having routine simultaneous bilateral surgery. Study subjects will also be 
required to complete postoperative questionnaires after each eyes’ surgery.  
 
Study medication risks are as mentioned above. For the opioid combination medication, 
use will preclude driving and use has been associated with sleepiness, fatigue, nausea/vomiting, 
constipation, itching, and potential for abuse. For the CBD product, use may be associated with 
somnolence, sedation, decreased appetite, diarrhea, liver enzyme elevations, fatigue, malaise, 
rash, insomnia, sleep problems and infections. 
 
8. Possible Benefits: 
 
Benefits of the study could be to identify an alternative pain control regimen satisfactory for 
post-PRK pain that could reduce the need for opioid prescriptions.  
 
9. Conflict of Interest: 


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The investigators have no financial interests related to the study. The study is funded by a 
grant from the Consortium for Medical Marijuana Clinical Outcomes Research. 
  
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IRB version 03.09.04 
PI version 05/22/2024 
Randomized, Controlled Cross-over Comparison of Cannabidiol to Oral Opioid for 
Postoperative Photorefractive Keratectomy Pain Control 
2. Statistical Analysis Plan 
JASP 0.19.0 will be used to calculate baseline statistics and cohort demographics such as age, 
sex, and initial vision. Fisher test will be used to ensure equal allocation between groups and drug 
treatments. Multiple Repeated Measures ANOVA will be used to test for differences between 
vision, pain, and other secondary outcomes after using each drug. For survey outcomes, no 
comparison was made between drugs because outcomes were binocular and associated with use 
of both drugs. Alpha will be 0.05 for this study. Beta was estimated approximately 0.80 based on a 
sample size of 70 units (35 patients each eye).