Randomized, Controlled Cross-over Comparison of Cannabinoid to Oral Opioid for Postoperative Photorefractive Keratectomy Pain Control
Phase: PHASE2
Conditions: Photorefractive Keratectomy, Myopia, Hyperopia
Sponsor: University of Florida

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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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