- Email: [email protected]
Ocular pain response to treatment in dry eye patients
Journal Pre-proof Ocular Pain Response to Treatment in Dry Eye Patients Andrew N. Siedlecki, Scott D. Smith, Adam R. Siedlecki, Salim M. Hayek, Rony R. Sayegh PII:
S1542-0124(20)30011-2
DOI:
https://doi.org/10.1016/j.jtos.2019.12.004
Reference:
JTOS 464
To appear in:
Ocular Surface
Received Date: 9 June 2019 Revised Date:
14 December 2019
Accepted Date: 16 December 2019
Please cite this article as: Siedlecki AN, Smith SD, Siedlecki AR, Hayek SM, Sayegh RR, Ocular Pain Response to Treatment in Dry Eye Patients, Ocular Surface, https://doi.org/10.1016/j.jtos.2019.12.004. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc.
Ocular Pain Response to Treatment in Dry Eye Patients Andrew N Siedlecki
M.D.a
Scott D Smith
M.D., M.P.H.b
Adam R Siedlecki
B.S.c
Salim M Hayek
M.D.d
Rony R Sayegh
M.D.a,b
a
: Department of Ophthalmology, Case Western Reserve University, University Hospitals Eye
Institute, Cleveland, Ohio, United States b
: Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic
Abu Dhabi, Abu Dhabi, United Arab Emirates c
: University of Buffalo Jacobs School of Medicine, Buffalo, New York, United States
d
: Department of Anesthesiology, University Hospitals, Cleveland, Ohio, United States
Corresponding Author: Rony Sayegh, M.D. Address: Cleveland Clinic Abu Dhabi, Al Falah Street, Abu Dhabi, United Arab Emirates Phone: +971-800 8 2223 Email: [email protected]
Short Title (running head): Ocular Pain Treatment Response
Declarations of Interest: None
Funding: None.
Abstract:
Purpose: Pain is a frequently reported symptom in dry eye disease (DED). We examine the factors associated with ocular pain severity and patient-reported improvement in ocular pain to commonly used dry eye and pain treatments. Methods: Cross-sectional study of patients presenting for dry eye management. Demographics, ocular and medical history, OSDI, numeric pain scale, pain descriptors, and subjective response to tried eye drop, systemic, and non-pharmacologic treatments were collected. Statistical analysis was performed to identify differential treatment response in patients with various pain levels using the non-parametric test for trend. Results: 144 patients were categorized into 4 groups according to reported pain severity. Increasing pain was significantly associated with younger age, history of refractive surgery, higher OSDI score, and less likelihood of corneal staining. Patients with higher pain intensity were more likely to report a history of fibromyalgia, depression, anxiety, and migraine. Patients with greater pain severity were less responsive to treatment with artificial tears (p<0.001), lubricating ointment (p=0.002), steroid eye drops (p=0.03), cyclosporine 0.05% (p=0.03), 20% autologous serum tears (p=0.01), hot compresses (p=0.04), lid hygiene (p=0.002) and punctal occlusion (p=0.03). Conclusions: Dry eye patients with severe ocular pain often have associated psychological and systemic pain conditions. Treating the underlying DED is beneficial in reducing ocular pain, however the low rate of a satisfactory response highlights the need for further investigation of effective therapies. Cross-sectional studies can provide guidance in the treatment of patients with dry eye-related ocular pain and guide future prospective studies on potentially effective therapies.
Keywords: Dry Eye; Ocular Neuropathic Pain; Pain; Artificial Tears; Cornea; Sunglasses
Introduction: Dry eye disease (DED) is a multifactorial condition affecting the homeostasis of the tear film and ocular surface resulting in various ocular symptoms experienced by patients.[1] The condition affects approximately 20 million people in the United States and 344 million people worldwide.[2] The prevalence of symptomatic DED with or without signs ranges from 5% to 50%, while DED with signs irrespective of symptoms is generally higher, up to 75%.[3] The condition is well-known to negatively impact quality of life, with an estimated annual cost of management in the United States of approximately $3.84 billion.[4] It presents a significant burden on the United States healthcare system and is known to significantly impact quality of life and work productivity.[3–6]
Although rarely evaluated in existing research and only examined in less than 10% of DED studies, ocular pain was ranked by patients as one of the top 3 most important outcomes that needs to be examined by researchers.[7] It is described by patients in various terms including irritation, burning, dryness, photosensitivity, and aching, among others.[8–10] DED pain can be experienced in the absence of observable tissue damage (e.g. corneal fluorescein staining). This disconnect between symptoms and signs is not uncommon in DED, and has led many to postulate that a neuropathic component is frequently present in the disease.[11–13] Furthermore, it is not uncommon for DED patients to experience dissimilar responses to treatment, highlighting the underlying difference in pathophysiology between those with and without a neuropathic pain component.[14,15]
Novel treatments for DED have frequently been introduced, significantly increasing the treating physician’s armamentarium.[16] Treatments are typically considered successful if there is improvement in the tear film or decrease in punctate staining of the cornea, and if there is improvement in the score on one of the currently available dry eye questionnaires.[17] However,
these treatment outcome measures may underrepresent or even miss patients with a predominant pain component. As such, it is unclear how DED patients with predominantly pain symptoms respond to traditional dry eye therapy. In this study, we examine the prevalence of pain associated with DED, as well as patient-reported improvement in ocular pain to commonly used dry eye and pain treatments.
Materials and methods: New or returning patients presenting to the clinic of one ophthalmologist (RRS) at an academic medical center system between February and August 2018 with a chief complaint of dry eye or symptoms consistent with such a diagnosis (dryness, grittiness, foreign body sensation, burning, tearing, and/or photosensitivity) were eligible for inclusion. The Ocular Surface Disease Index (OSDI) was administered to all patients but was not used for patient selection, since most of these patients were already on some form of treatment. A comprehensive ocular examination was performed and patients with any causes of ocular pain other than dry eye (such as abrasions, uveitis, etc.) were excluded. The Numerical Rating Scale for pain,[18] modified Neuropathic Pain Symptom Inventory,[19] and the health rating question from the 36-Item Short Form Health Survey (SF-36) questionnaire[20] were completed by patients. The ocular pain severity averaged over the previous week was ascertained on an 11-point scale (0-10 with 10 being the most intense). Patients were assigned into the following pain groups based on reported pain severity: none (0), mild (1-4), moderate (5-7), and severe (8-10).
A comprehensive list of currently available dry eye and pain treatments was given to subjects, and the perceived efficacy of dry eye treatments on ocular pain was self-reported as either “a lot,” “partially,” or “not at all” if the treatment had been used by the patient, otherwise “never tried” was selected. A positive response to treatment was defined by complete or partial improvement in ocular pain Demographic information, medical history including ocular surgical history, general medical conditions (specifically rheumatologic disease, diabetes, thyroid disease, allergies, depression, fibromyalgia, irritable bowel syndrome, migraine, and other pain disorders), and use of systemic medications were collected, confirmed with chart review, and entered into an itemized data collection sheet.
Study data were managed using REDCap (Research Electronic Data Capture) tools hosted at University Hospitals of Cleveland.[21] Data were deidentified and transferred to Stata v13.1 statistical software (StataCorp, College Station, TX) for analysis. Single variable comparison of continuous variables was performed using the Student’s t-test while categorical data were analyzed using Fisher’s exact test. Pain severity was coded as an ordinal variable. Analysis of factors associated with pain severity and differences in response to treatment by pain severity were analyzed using the Cuzick nonparametric test for trend across ordered groups.
Results: A total of 144 subjects were included in this study. The mean age of subjects was 58.1 years (range: 19 to 98 years). Females represented 83.3% of enrolled patients. Caucasians represented 70.1%, African Americans 20.8%, Hispanics 4.7%, and Asians 4.2% of the study population. The majority of patients were married (50.7%), with 27.1% single, 12.5% divorced, and 9.8% widowed.
Demographic data stratified by ocular pain severity are displayed in Table 1. Greater ocular pain severity was associated with younger age (p<0.05). There was no significant predilection for sex, race, or likelihood of being married among pain groups (p>0.05).
The mean self-reported ocular pain severity score was 3.8±2.9. The distribution of reported mean pain intensity is illustrated in Figure 1.
The mean OSDI score was 37.2 ± 22.6. Mean OSDI scores for None, Mild, Moderate, and Severe groups were 19.6, 34.2, 46.4, and 56.1 respectively, with a significant association between higher mean score and more severe pain (p<0.0001). Patients reporting more severe pain more often reported associated burning, itching, photosensitivity, difficulty keeping eyes open, and constant symptoms (all p<0.05), but not pain elsewhere in the body. Among subjects who reported eye pain, it was reported to be affecting the left eye in 40.0%, the right eye in 24.3%, and both eyes in 35.6% (p=0.006).
Significant associations were also seen between greater ocular pain severity and the report of depression, anxiety, migraine, and fibromyalgia (all p<0.05). Greater pain was associated with a history of refractive surgery (p=0.03) and the perception that the patient’s general health status
was “bad” (p=0.02). Pain severity was not associated with a history of rheumatologic disease, allergy, or prior ocular surgery (all p>0.05).
Greater pain severity was associated with a lower probability of significant corneal staining with fluorescein on slit lamp examination (National Eye Institute grading scale≥2, p=0.004). In addition, increasing pain severity tended to be associated with less improvement in eye pain following proparacaine administration, but the difference did not reach statistical significance (p=0.06).
Response to various dry eye treatments for each pain group is represented in Figures 2-5, and in more detail for the severe pain group in Table 2. In general, patients with severe ocular pain were more likely to have tried multiple therapies including medical and non-pharmacologic compared with all other groups (p=0.004). Greater pain severity was associated with a lower likelihood of improvement in symptoms with artificial tears (p<0.001), lubricating ointment (p=0.002), steroid eye drops (p=0.03), cyclosporine A 0.05% (p=0.03), 20% autologous serum tears (p=0.01), hot compresses (p=0.04), and lid hygiene (p=0.002). The rate of response to punctal occlusion also was lower with increasing pain severity (p=0.03). There was no significant difference in response rate among pain severity groups to treatment with omega-3 fatty acid supplements, lifitegrast, or tetracyclines (all p>0.2). There were no significant differences in response to sunglasses, scleral contact lenses, onion goggles (moisture chambers), air humidifiers, exercise, yoga, or acupuncture (all p>0.05). There were also no significant differences in reported efficacy for treatment with oral analgesics, opiates, gabapentin/pregabalin, and antidepressants (all p>0.2),
Discussion: Multiple studies have investigated the efficacy of various treatments on dry eye symptoms.[22,23] To our knowledge, this is the first study systematically looking at the subjective efficacy of these treatments specifically for the pain component of dry eye. Some degree of ocular pain is reported by the majority of patients with DED, and our population showed a prevalence and distribution of ocular pain symptoms that is consistent with previous reports.[15] We also found a similar association of increased ocular pain with younger age, history of refractive surgery, higher OSDI scores and lower corneal staining (discordance between signs and symptoms), and a diagnosis of psychological disorders such as depression, fibromyalgia, anxiety, and migraines.[15,24,25] Also, lower self-perceived health has been found to be significantly associated with increased discordance between symptoms and signs of DED,[26] and we similarly found greater pain to be associated with the perception of the patient’s general health status as “bad”. Though symptomatic ocular surface disease is more common in females, no association between sex and pain severity or treatment response was observed in this study.
There has been conflicting evidence on the importance of social support in chronic pain.[27] In our cohort, the proportion of married subjects did not differ in the severe pain group. Interestingly, we observed a left-sided preponderance of pain in our population. This has been observed in other pain syndromes and has been attributed to the right brain hemisphere’s reduced efficiency in processing sensory input and its dominance in emotional experience.[28]
In a recent study of 118 patients with dry eye-associated ocular pain, 19% reported no improvement to ocular pain with artificial tears, 62% reported partial improvement and 19% reported complete improvement.[14] Our series reports similar results with 14% of patients who used artificial tears reporting no improvement, 55% partial improvement, and 31% “a lot” of
improvement. Furthermore, in our series, 71% of patients in the severe pain group experienced partial or complete pain relief with artificial tears. Although less effective in patients with a more severe pain component of ocular discomfort than in those without ocular pain, artificial tears remain the topical ophthalmic medication with the highest efficacy in the treatment of dry eyerelated ocular pain, and the first-line eye drop of choice in this patient population. This highlights the importance of treating the underlying dry eye component in patients with ocular pain to improve their symptoms.
Autologous serum tears have been considered to be one of the most effective topical agents for the control of intractable ocular pain. They have been reported in a retrospective study to be effective in controlling light sensitivity in patients without ocular surface disease diagnosed with ocular neuropathic pain.[29] In our severe pain group, they were found to be the second most effective topical ophthalmic therapy for ocular pain, with a response rate of 55%. In contrast, in our entire cohort, steroid eye drops were found to be the second most effective. Antiinflammatory medications are often used in the treatment of chronic pain, since inflammation can cause damage to nociceptors, modify and modulate neurons in the nervous system, and amplify the excitability of neurons in the central nervous system.[30] In our series, a higher response rate was reported for steroid eye drops compared to cyclosporine A 0.05% and lifitegrast, which may be explained by the broader spectrum of corticosteroid blockade of inflammatory pain mediators.
With regards to systemic therapy, omega-3 fatty acid supplementation has been found to be effective in reducing symptoms of neuropathic pain [31], however, no significant effect on ocular discomfort was noted in a randomized-controlled study.[32] Approximately half of our patients reported improvement of their ocular pain with use of this supplement, with no difference noted across the spectrum of pain severity. Furthermore, response to the other systemic therapies
was found to be low across all pain severities in our study. This is consistent with the findings of various meta-analyses on chronic neuropathic pain, showing lack of unbiased evidence supporting the efficacy of various treatments including paracetamol (acetaminophen)[33], nonsteroidal anti-inflammatories[34], opioids[35], and tricyclic antidepressants[36]. Although one meta-analysis showed support for the use of gabapentin and pregabalin for certain neuropathic pain conditions,[37] more recent ophthalmic literature supports our finding of potentially limited benefit for ocular neuropathic pain.[38]
Finally, our study shows an important role for non-pharmacological approaches in the treatment of ocular pain. Hot compresses and sunglasses were found to be helpful by a large number of our patients. Indeed, heat has been found to selectively control small-diameter sensory fibers, contributing to pain control.[39] Also, recent evidence indicates that intrinsically photosensitive retinal ganglion cells play a role in the pathophysiology of photophobia, and using FL-41 tinted lenses can help relieve symptoms in conditions associated with photophobia such as migraine, blepharospasm, and traumatic brain injury.[40] As such, these are simple interventions that patients should be encouraged to try. Exercise, yoga, and acupuncture seemed less helpful in our patient population. However, generalizability is difficult given the large variability and lack of standardization of these practices.
Several limitations of this study should be considered. It is inherently limited by its crosssectional and retrospective design. Our main outcome variables were assessed based on subjective patient recollection. Although the study enrolled a relatively large number of subjects, variability in patients’ prior history of use of different treatments for dry eye led to a small sample size in some treatment categories, which limits the interpretation of the efficacy of these treatments. Additionally, lack of a treatment algorithm, variability in the frequency of use of medications or other interventions used by study subjects, variable adherence to treatment
recommendations, and lack of treatment standardization (such as temperature of the compresses, etc.) limits the assessment of their efficacy.
With these limitations in mind, it is nevertheless evident that important differences in the clinical presentation and efficacy of treatment exist among dry eye patients related to the severity of pain that they report. Patients with severe pain represent only a small fraction of the overall dry eye population. Although less responsive to therapy compared to those with less severe ocular pain, some improvement is reported in many with the treatment of the underlying DED, and traditional dry eye therapy should be initiated first. However, since only about half of these patients will have a satisfactory response with the treatment modalities available to the ophthalmologist, a multi-disciplinary approach to the condition should be considered, with assistance from pain medicine specialists and psychologists, among others. Furthermore, this study highlights the need for further research into effective therapies for dry eye patients with severe ocular pain and those with pain that may be neuropathic.
Acknowledgements: None
Disclosures and Conflicts of Interest: All authors report no relevant conflicts of interest, financial or otherwise.
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Tables: Table 1. Demographics, medical and surgical history, OSDI score, and examination findings of all subjects.
None (0) [n=27]
Mild (1-4) [n=64]
Moderate (5-7) [n=34]
Severe (8-10) [n=19]
Total [n=144]
61.1 (16.0) 22 (81.5) 18 (66.7) 13 (48.1)
58.2 (14.3) 52 (81.2)
57.9 (12.8) 32 (94.1)
53.7 (18.6)† 14 (73.7)
58.1 (14.9) 120 (83.3)
49 (76.6) 27 (42.2)
22 (64.7) 18 (52.9)
12 (63.2) 13 (68.4)
101 (70.1) 71 (49.3)
0.03 0.9 0.5 0.08
0 (0.0) 8 (29.6)
5 (7.8) 18 (28.1)
5 (14.7) 7 (20.6)
3 (15.8)† 3 (15.8)
13 (9.0) 36 (25.0)
0.03 0.2
2 (7.4) 6 (22.2) 7 (28.0) 3 (7.5) 6 (22.2) 18 (66.6) 1 (2.5)
5 (7.8) 20 (31.2) 16 (25.8) 9 (28.1) 16 (25.0) 38 (59.4) 2 (6.3)
7 (20.6) 16 (47.0) 12 (36.4) 11 (36.7) 6 (17.6) 22 (64.7) 2 (6.6)
3 (15.8) 8 (42.1) 8 (57.1) 15 (35.7)† 6 (31.6) 11 (57.9) 6 (14.6)†
17 (11.8) 50 (34.7) 43 (32.0) 38 (26.4) 34 (23.6) 89 (61.8) 11 (7.7)
0.03 0.05 0.05 0.01 0.9 0.7 0.02
19.6 (15.7)
34.2 (18.6)
46.4 (20.0)
56.1 (27.0)†
37.2 (22.6)
<0.0001
25.9%
17.2%
0.0%
0.0%†
12.5%
0.004
p-value
Patient Demographics Mean age (SD) Female sex (%) Caucasian race (%) Not married (%) Ocular Surgical History Refractive Surgery (%) Cataract Surgery (%) Medical History Fibromyalgia (%) Depression (%) Anxiety (%) Migraine (%) Rheumatologic Condition (%) Allergic Condition (%) "Bad" health status (%) OSDI Score Examination Corneal staining
Proparacaine response
N/A
70.3%
69.0%
50.0%†
67.1%
0.06
SD: standard deviation †
: p≤0.05
Unmarried subjects included those self-reported as single, divorced, or widowed. Rheumatologic conditions specifically reported included Sjögren syndrome, rheumatoid arthritis, scleroderma, mixed connective tissue disease, systemic lupus erythematosus, and sarcoidosis. Allergic conditions included allergy, hay fever, asthma, and eczema. Health status was self-reported as either “excellent”, “very good”, “good”, “reasonable”, or “bad”.
Table 2. Breakdown for patient-reported ocular pain improvement with various treatment modalities in the severe pain group.
Sunglasses Acetaminophen, non-steroidal anti-inflammatory pills Hot Compresses Artificial tears Autologous serum tears Omega-3 supplementation Opioids Steroid eye drops Ointment Lifitegrast Tetracyclines Cyclosporine A 0.05% Antidepressants Humidifier Punctal occlusion Scleral lenses Lid scrubs/wipes/baby shampoo Exercise Lyrica, Neurontin, or Gabapentin Yoga Onion goggles Acupuncture
A lot 0/14 2/15 2/13 2/19 1/8 1/9 1/7 0/12 1/15 1/5 1/5 2/11 1/11 2/11 0/6 0/3 0/10 0/10 1/12 0/7 0/3 0/4
Reported Ocular Pain Improvement Partially Not at all Never tried Response rate 9/14 5/14 4/18 64.3% 7/15 6/15 4/19 60.0% 5/13 6/13 6/19 53.8% 8/19 9/19 0/19 52.6% 3/8 4/8 11/19 50.0% 3/9 5/9 10/19 44.4% 2/7 4/7 12/19 42.9% 5/12 7/12 7/19 41.7% 5/15 9/15 4/19 40.0% 1/5 3/5 14/19 40.0% 1/5 3/5 14/19 40.0% 2/11 7/11 8/19 36.4% 3/11 7/11 8/19 36.4% 2/11 7/11 8/19 36.4% 2/6 4/6 13/19 33.3% 1/3 2/3 16/19 33.3% 3/10 7/10 9/19 30.0% 3/10 7/10 9/19 30.0% 2/12 9/12 7/19 25.0% 1/7 6/7 12/19 14.3% 0/3 3/3 16/19 0.0% 0/4 4/4 15/19 0.0%
Figure Captions:
Figure 1. Distribution of reported pain severity level in patients presenting with dry eye symptoms (n=144). Subjects were subdivided by pain severity into none (0), mild (1 - 4), moderate (5 - 7), and severe (8 - 10). Figure 2. Treatment response for the entire patient cohort. The percentage of subjects reporting complete or partial improvement in ocular pain is shown with each treatment modality surveyed. Figure 3. Treatment response to topical therapies by pain group. The percentage of subjects reporting complete or partial improvement in ocular pain with each treatment is displayed, subdivided by pain severity group. Patients who reported not trying these treatments were excluded. Groups designated with an asterisk represent statistically significant differences at p≤0.05. Figure 4. Treatment response to oral therapies by pain group. The percentage of subjects reporting complete or partial improvement in ocular pain with each treatment is displayed, subdivided by pain severity group. Patients who reported not trying these treatments were excluded. Groups designated with an asterisk represent statistically significant differences at p≤0.05. Figure 5. Treatment response to non-pharmacologic supportive therapies by pain group. The percentage of subjects reporting complete or partial improvement in ocular pain with each treatment is displayed, subdivided by pain severity group. Patients who reported not trying these treatments were excluded. Groups designated with an asterisk represent statistically significant differences at p≤0.05.
Table 1. Demographics, medical and surgical history, OSDI score, and examination findings of all subjects.
None (0) [n=27]
Mild (1-4) [n=64]
Moderate (5-7) [n=34]
Severe (8-10) [n=19]
Total [n=144]
p-value
61.1 (16.0) 22 (81.5) 18 (66.7) 13 (48.1)
58.2 (14.3) 52 (81.2) 49 (76.6) 27 (42.2)
57.9 (12.8) 32 (94.1) 22 (64.7) 18 (52.9)
53.7 (18.6)† 14 (73.7) 12 (63.2) 13 (68.4)
58.1 (14.9) 120 (83.3) 101 (70.1) 71 (49.3)
0.03 0.9 0.5 0.08
0 (0.0) 8 (29.6)
5 (7.8) 18 (28.1)
5 (14.7) 7 (20.6)
3 (15.8)† 3 (15.8)
13 (9.0) 36 (25.0)
0.03 0.2
Fibromyalgia (%)
2 (7.4)
5 (7.8)
7 (20.6)
3 (15.8)
17 (11.8)
0.03
Depression (%) Anxiety (%) Migraine (%) Rheumatologic Condition (%)
6 (22.2) 7 (28.0) 3 (7.5) 6 (22.2)
20 (31.2) 16 (25.8) 9 (28.1) 16 (25.0)
16 (47.0) 12 (36.4) 11 (36.7) 6 (17.6)
8 (42.1) 8 (57.1) 15 (35.7)† 6 (31.6)
50 (34.7) 43 (32.0) 38 (26.4) 34 (23.6)
0.05 0.05 0.01 0.9
Allergic Condition (%) "Bad" health status (%)
18 (66.6) 1 (2.5)
38 (59.4) 2 (6.3)
22 (64.7) 2 (6.6)
11 (57.9) 6 (14.6)†
89 (61.8) 11 (7.7)
0.7 0.02
19.6 (15.7)
34.2 (18.6)
46.4 (20.0)
56.1 (27.0)†
37.2 (22.6)
<0.0001
25.9% N/A
17.2% 70.3%
0.0% 69.0%
0.0%† 50.0%†
12.5% 67.1%
0.004 0.06
Patient Demographics Mean age (SD) Female sex (%) Caucasian race (%) Not married (%) Ocular Surgical History Refractive Surgery (%) Cataract Surgery (%) Medical History
OSDI Score Examination Corneal staining Proparacaine response
SD: standard deviation †
: p≤0.05
Unmarried subjects included those self-reported as single, divorced, or widowed. Rheumatologic conditions specifically reported included Sjögren syndrome, rheumatoid arthritis, scleroderma, mixed connective tissue disease, systemic lupus erythematosus, and sarcoidosis. Allergic conditions included allergy, hay fever, asthma, and eczema. Health status was self-reported as either “excellent”, “very good”, “good”, “reasonable”, or “bad”.
Table 2. Breakdown for patient-reported ocular pain improvement with various treatment modalities in the severe pain group.
Sunglasses Acetaminophen, non-steroidal anti-inflammatory pills Hot Compresses Artificial tears Autologous serum tears Omega-3 supplementation Opioids Steroid eyedrops Ointment Lifitegrast Tetracyclines Cyclosporine A 0.05% Antidepressants Humidifier Punctal occlusion Scleral lenses Lid scrubs/wipes/baby shampoo Exercise Lyrica, Neurontin, or Gabapentin Yoga Onion goggles Acupuncture
A lot 0/14 2/15 2/13 2/19 1/8 1/9 1/7 0/12 1/15 1/5 1/5 2/11 1/11 2/11 0/6 0/3 0/10 0/10 1/12 0/7 0/3 0/4
Reported Ocular Pain Improvement Partially Not at all Never tried Response rate 9/14 5/14 4/18 64.3% 7/15 6/15 4/19 60.0% 5/13 6/13 6/19 53.8% 8/19 9/19 0/19 52.6% 3/8 4/8 11/19 50.0% 3/9 5/9 10/19 44.4% 2/7 4/7 12/19 42.9% 5/12 7/12 7/19 41.7% 5/15 9/15 4/19 40.0% 1/5 3/5 14/19 40.0% 1/5 3/5 14/19 40.0% 2/11 7/11 8/19 36.4% 3/11 7/11 8/19 36.4% 2/11 7/11 8/19 36.4% 2/6 4/6 13/19 33.3% 1/3 2/3 16/19 33.3% 3/10 7/10 9/19 30.0% 3/10 7/10 9/19 30.0% 2/12 9/12 7/19 25.0% 1/7 6/7 12/19 14.3% 0/3 3/3 16/19 0.0% 0/4 4/4 15/19 0.0%
S1542-0124(20)30011-2
DOI:
https://doi.org/10.1016/j.jtos.2019.12.004
Reference:
JTOS 464
To appear in:
Ocular Surface
Received Date: 9 June 2019 Revised Date:
14 December 2019
Accepted Date: 16 December 2019
Please cite this article as: Siedlecki AN, Smith SD, Siedlecki AR, Hayek SM, Sayegh RR, Ocular Pain Response to Treatment in Dry Eye Patients, Ocular Surface, https://doi.org/10.1016/j.jtos.2019.12.004. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc.
Ocular Pain Response to Treatment in Dry Eye Patients Andrew N Siedlecki
M.D.a
Scott D Smith
M.D., M.P.H.b
Adam R Siedlecki
B.S.c
Salim M Hayek
M.D.d
Rony R Sayegh
M.D.a,b
a
: Department of Ophthalmology, Case Western Reserve University, University Hospitals Eye
Institute, Cleveland, Ohio, United States b
: Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic
Abu Dhabi, Abu Dhabi, United Arab Emirates c
: University of Buffalo Jacobs School of Medicine, Buffalo, New York, United States
d
: Department of Anesthesiology, University Hospitals, Cleveland, Ohio, United States
Corresponding Author: Rony Sayegh, M.D. Address: Cleveland Clinic Abu Dhabi, Al Falah Street, Abu Dhabi, United Arab Emirates Phone: +971-800 8 2223 Email: [email protected]
Short Title (running head): Ocular Pain Treatment Response
Declarations of Interest: None
Funding: None.
Abstract:
Purpose: Pain is a frequently reported symptom in dry eye disease (DED). We examine the factors associated with ocular pain severity and patient-reported improvement in ocular pain to commonly used dry eye and pain treatments. Methods: Cross-sectional study of patients presenting for dry eye management. Demographics, ocular and medical history, OSDI, numeric pain scale, pain descriptors, and subjective response to tried eye drop, systemic, and non-pharmacologic treatments were collected. Statistical analysis was performed to identify differential treatment response in patients with various pain levels using the non-parametric test for trend. Results: 144 patients were categorized into 4 groups according to reported pain severity. Increasing pain was significantly associated with younger age, history of refractive surgery, higher OSDI score, and less likelihood of corneal staining. Patients with higher pain intensity were more likely to report a history of fibromyalgia, depression, anxiety, and migraine. Patients with greater pain severity were less responsive to treatment with artificial tears (p<0.001), lubricating ointment (p=0.002), steroid eye drops (p=0.03), cyclosporine 0.05% (p=0.03), 20% autologous serum tears (p=0.01), hot compresses (p=0.04), lid hygiene (p=0.002) and punctal occlusion (p=0.03). Conclusions: Dry eye patients with severe ocular pain often have associated psychological and systemic pain conditions. Treating the underlying DED is beneficial in reducing ocular pain, however the low rate of a satisfactory response highlights the need for further investigation of effective therapies. Cross-sectional studies can provide guidance in the treatment of patients with dry eye-related ocular pain and guide future prospective studies on potentially effective therapies.
Keywords: Dry Eye; Ocular Neuropathic Pain; Pain; Artificial Tears; Cornea; Sunglasses
Introduction: Dry eye disease (DED) is a multifactorial condition affecting the homeostasis of the tear film and ocular surface resulting in various ocular symptoms experienced by patients.[1] The condition affects approximately 20 million people in the United States and 344 million people worldwide.[2] The prevalence of symptomatic DED with or without signs ranges from 5% to 50%, while DED with signs irrespective of symptoms is generally higher, up to 75%.[3] The condition is well-known to negatively impact quality of life, with an estimated annual cost of management in the United States of approximately $3.84 billion.[4] It presents a significant burden on the United States healthcare system and is known to significantly impact quality of life and work productivity.[3–6]
Although rarely evaluated in existing research and only examined in less than 10% of DED studies, ocular pain was ranked by patients as one of the top 3 most important outcomes that needs to be examined by researchers.[7] It is described by patients in various terms including irritation, burning, dryness, photosensitivity, and aching, among others.[8–10] DED pain can be experienced in the absence of observable tissue damage (e.g. corneal fluorescein staining). This disconnect between symptoms and signs is not uncommon in DED, and has led many to postulate that a neuropathic component is frequently present in the disease.[11–13] Furthermore, it is not uncommon for DED patients to experience dissimilar responses to treatment, highlighting the underlying difference in pathophysiology between those with and without a neuropathic pain component.[14,15]
Novel treatments for DED have frequently been introduced, significantly increasing the treating physician’s armamentarium.[16] Treatments are typically considered successful if there is improvement in the tear film or decrease in punctate staining of the cornea, and if there is improvement in the score on one of the currently available dry eye questionnaires.[17] However,
these treatment outcome measures may underrepresent or even miss patients with a predominant pain component. As such, it is unclear how DED patients with predominantly pain symptoms respond to traditional dry eye therapy. In this study, we examine the prevalence of pain associated with DED, as well as patient-reported improvement in ocular pain to commonly used dry eye and pain treatments.
Materials and methods: New or returning patients presenting to the clinic of one ophthalmologist (RRS) at an academic medical center system between February and August 2018 with a chief complaint of dry eye or symptoms consistent with such a diagnosis (dryness, grittiness, foreign body sensation, burning, tearing, and/or photosensitivity) were eligible for inclusion. The Ocular Surface Disease Index (OSDI) was administered to all patients but was not used for patient selection, since most of these patients were already on some form of treatment. A comprehensive ocular examination was performed and patients with any causes of ocular pain other than dry eye (such as abrasions, uveitis, etc.) were excluded. The Numerical Rating Scale for pain,[18] modified Neuropathic Pain Symptom Inventory,[19] and the health rating question from the 36-Item Short Form Health Survey (SF-36) questionnaire[20] were completed by patients. The ocular pain severity averaged over the previous week was ascertained on an 11-point scale (0-10 with 10 being the most intense). Patients were assigned into the following pain groups based on reported pain severity: none (0), mild (1-4), moderate (5-7), and severe (8-10).
A comprehensive list of currently available dry eye and pain treatments was given to subjects, and the perceived efficacy of dry eye treatments on ocular pain was self-reported as either “a lot,” “partially,” or “not at all” if the treatment had been used by the patient, otherwise “never tried” was selected. A positive response to treatment was defined by complete or partial improvement in ocular pain Demographic information, medical history including ocular surgical history, general medical conditions (specifically rheumatologic disease, diabetes, thyroid disease, allergies, depression, fibromyalgia, irritable bowel syndrome, migraine, and other pain disorders), and use of systemic medications were collected, confirmed with chart review, and entered into an itemized data collection sheet.
Study data were managed using REDCap (Research Electronic Data Capture) tools hosted at University Hospitals of Cleveland.[21] Data were deidentified and transferred to Stata v13.1 statistical software (StataCorp, College Station, TX) for analysis. Single variable comparison of continuous variables was performed using the Student’s t-test while categorical data were analyzed using Fisher’s exact test. Pain severity was coded as an ordinal variable. Analysis of factors associated with pain severity and differences in response to treatment by pain severity were analyzed using the Cuzick nonparametric test for trend across ordered groups.
Results: A total of 144 subjects were included in this study. The mean age of subjects was 58.1 years (range: 19 to 98 years). Females represented 83.3% of enrolled patients. Caucasians represented 70.1%, African Americans 20.8%, Hispanics 4.7%, and Asians 4.2% of the study population. The majority of patients were married (50.7%), with 27.1% single, 12.5% divorced, and 9.8% widowed.
Demographic data stratified by ocular pain severity are displayed in Table 1. Greater ocular pain severity was associated with younger age (p<0.05). There was no significant predilection for sex, race, or likelihood of being married among pain groups (p>0.05).
The mean self-reported ocular pain severity score was 3.8±2.9. The distribution of reported mean pain intensity is illustrated in Figure 1.
The mean OSDI score was 37.2 ± 22.6. Mean OSDI scores for None, Mild, Moderate, and Severe groups were 19.6, 34.2, 46.4, and 56.1 respectively, with a significant association between higher mean score and more severe pain (p<0.0001). Patients reporting more severe pain more often reported associated burning, itching, photosensitivity, difficulty keeping eyes open, and constant symptoms (all p<0.05), but not pain elsewhere in the body. Among subjects who reported eye pain, it was reported to be affecting the left eye in 40.0%, the right eye in 24.3%, and both eyes in 35.6% (p=0.006).
Significant associations were also seen between greater ocular pain severity and the report of depression, anxiety, migraine, and fibromyalgia (all p<0.05). Greater pain was associated with a history of refractive surgery (p=0.03) and the perception that the patient’s general health status
was “bad” (p=0.02). Pain severity was not associated with a history of rheumatologic disease, allergy, or prior ocular surgery (all p>0.05).
Greater pain severity was associated with a lower probability of significant corneal staining with fluorescein on slit lamp examination (National Eye Institute grading scale≥2, p=0.004). In addition, increasing pain severity tended to be associated with less improvement in eye pain following proparacaine administration, but the difference did not reach statistical significance (p=0.06).
Response to various dry eye treatments for each pain group is represented in Figures 2-5, and in more detail for the severe pain group in Table 2. In general, patients with severe ocular pain were more likely to have tried multiple therapies including medical and non-pharmacologic compared with all other groups (p=0.004). Greater pain severity was associated with a lower likelihood of improvement in symptoms with artificial tears (p<0.001), lubricating ointment (p=0.002), steroid eye drops (p=0.03), cyclosporine A 0.05% (p=0.03), 20% autologous serum tears (p=0.01), hot compresses (p=0.04), and lid hygiene (p=0.002). The rate of response to punctal occlusion also was lower with increasing pain severity (p=0.03). There was no significant difference in response rate among pain severity groups to treatment with omega-3 fatty acid supplements, lifitegrast, or tetracyclines (all p>0.2). There were no significant differences in response to sunglasses, scleral contact lenses, onion goggles (moisture chambers), air humidifiers, exercise, yoga, or acupuncture (all p>0.05). There were also no significant differences in reported efficacy for treatment with oral analgesics, opiates, gabapentin/pregabalin, and antidepressants (all p>0.2),
Discussion: Multiple studies have investigated the efficacy of various treatments on dry eye symptoms.[22,23] To our knowledge, this is the first study systematically looking at the subjective efficacy of these treatments specifically for the pain component of dry eye. Some degree of ocular pain is reported by the majority of patients with DED, and our population showed a prevalence and distribution of ocular pain symptoms that is consistent with previous reports.[15] We also found a similar association of increased ocular pain with younger age, history of refractive surgery, higher OSDI scores and lower corneal staining (discordance between signs and symptoms), and a diagnosis of psychological disorders such as depression, fibromyalgia, anxiety, and migraines.[15,24,25] Also, lower self-perceived health has been found to be significantly associated with increased discordance between symptoms and signs of DED,[26] and we similarly found greater pain to be associated with the perception of the patient’s general health status as “bad”. Though symptomatic ocular surface disease is more common in females, no association between sex and pain severity or treatment response was observed in this study.
There has been conflicting evidence on the importance of social support in chronic pain.[27] In our cohort, the proportion of married subjects did not differ in the severe pain group. Interestingly, we observed a left-sided preponderance of pain in our population. This has been observed in other pain syndromes and has been attributed to the right brain hemisphere’s reduced efficiency in processing sensory input and its dominance in emotional experience.[28]
In a recent study of 118 patients with dry eye-associated ocular pain, 19% reported no improvement to ocular pain with artificial tears, 62% reported partial improvement and 19% reported complete improvement.[14] Our series reports similar results with 14% of patients who used artificial tears reporting no improvement, 55% partial improvement, and 31% “a lot” of
improvement. Furthermore, in our series, 71% of patients in the severe pain group experienced partial or complete pain relief with artificial tears. Although less effective in patients with a more severe pain component of ocular discomfort than in those without ocular pain, artificial tears remain the topical ophthalmic medication with the highest efficacy in the treatment of dry eyerelated ocular pain, and the first-line eye drop of choice in this patient population. This highlights the importance of treating the underlying dry eye component in patients with ocular pain to improve their symptoms.
Autologous serum tears have been considered to be one of the most effective topical agents for the control of intractable ocular pain. They have been reported in a retrospective study to be effective in controlling light sensitivity in patients without ocular surface disease diagnosed with ocular neuropathic pain.[29] In our severe pain group, they were found to be the second most effective topical ophthalmic therapy for ocular pain, with a response rate of 55%. In contrast, in our entire cohort, steroid eye drops were found to be the second most effective. Antiinflammatory medications are often used in the treatment of chronic pain, since inflammation can cause damage to nociceptors, modify and modulate neurons in the nervous system, and amplify the excitability of neurons in the central nervous system.[30] In our series, a higher response rate was reported for steroid eye drops compared to cyclosporine A 0.05% and lifitegrast, which may be explained by the broader spectrum of corticosteroid blockade of inflammatory pain mediators.
With regards to systemic therapy, omega-3 fatty acid supplementation has been found to be effective in reducing symptoms of neuropathic pain [31], however, no significant effect on ocular discomfort was noted in a randomized-controlled study.[32] Approximately half of our patients reported improvement of their ocular pain with use of this supplement, with no difference noted across the spectrum of pain severity. Furthermore, response to the other systemic therapies
was found to be low across all pain severities in our study. This is consistent with the findings of various meta-analyses on chronic neuropathic pain, showing lack of unbiased evidence supporting the efficacy of various treatments including paracetamol (acetaminophen)[33], nonsteroidal anti-inflammatories[34], opioids[35], and tricyclic antidepressants[36]. Although one meta-analysis showed support for the use of gabapentin and pregabalin for certain neuropathic pain conditions,[37] more recent ophthalmic literature supports our finding of potentially limited benefit for ocular neuropathic pain.[38]
Finally, our study shows an important role for non-pharmacological approaches in the treatment of ocular pain. Hot compresses and sunglasses were found to be helpful by a large number of our patients. Indeed, heat has been found to selectively control small-diameter sensory fibers, contributing to pain control.[39] Also, recent evidence indicates that intrinsically photosensitive retinal ganglion cells play a role in the pathophysiology of photophobia, and using FL-41 tinted lenses can help relieve symptoms in conditions associated with photophobia such as migraine, blepharospasm, and traumatic brain injury.[40] As such, these are simple interventions that patients should be encouraged to try. Exercise, yoga, and acupuncture seemed less helpful in our patient population. However, generalizability is difficult given the large variability and lack of standardization of these practices.
Several limitations of this study should be considered. It is inherently limited by its crosssectional and retrospective design. Our main outcome variables were assessed based on subjective patient recollection. Although the study enrolled a relatively large number of subjects, variability in patients’ prior history of use of different treatments for dry eye led to a small sample size in some treatment categories, which limits the interpretation of the efficacy of these treatments. Additionally, lack of a treatment algorithm, variability in the frequency of use of medications or other interventions used by study subjects, variable adherence to treatment
recommendations, and lack of treatment standardization (such as temperature of the compresses, etc.) limits the assessment of their efficacy.
With these limitations in mind, it is nevertheless evident that important differences in the clinical presentation and efficacy of treatment exist among dry eye patients related to the severity of pain that they report. Patients with severe pain represent only a small fraction of the overall dry eye population. Although less responsive to therapy compared to those with less severe ocular pain, some improvement is reported in many with the treatment of the underlying DED, and traditional dry eye therapy should be initiated first. However, since only about half of these patients will have a satisfactory response with the treatment modalities available to the ophthalmologist, a multi-disciplinary approach to the condition should be considered, with assistance from pain medicine specialists and psychologists, among others. Furthermore, this study highlights the need for further research into effective therapies for dry eye patients with severe ocular pain and those with pain that may be neuropathic.
Acknowledgements: None
Disclosures and Conflicts of Interest: All authors report no relevant conflicts of interest, financial or otherwise.
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Tables: Table 1. Demographics, medical and surgical history, OSDI score, and examination findings of all subjects.
None (0) [n=27]
Mild (1-4) [n=64]
Moderate (5-7) [n=34]
Severe (8-10) [n=19]
Total [n=144]
61.1 (16.0) 22 (81.5) 18 (66.7) 13 (48.1)
58.2 (14.3) 52 (81.2)
57.9 (12.8) 32 (94.1)
53.7 (18.6)† 14 (73.7)
58.1 (14.9) 120 (83.3)
49 (76.6) 27 (42.2)
22 (64.7) 18 (52.9)
12 (63.2) 13 (68.4)
101 (70.1) 71 (49.3)
0.03 0.9 0.5 0.08
0 (0.0) 8 (29.6)
5 (7.8) 18 (28.1)
5 (14.7) 7 (20.6)
3 (15.8)† 3 (15.8)
13 (9.0) 36 (25.0)
0.03 0.2
2 (7.4) 6 (22.2) 7 (28.0) 3 (7.5) 6 (22.2) 18 (66.6) 1 (2.5)
5 (7.8) 20 (31.2) 16 (25.8) 9 (28.1) 16 (25.0) 38 (59.4) 2 (6.3)
7 (20.6) 16 (47.0) 12 (36.4) 11 (36.7) 6 (17.6) 22 (64.7) 2 (6.6)
3 (15.8) 8 (42.1) 8 (57.1) 15 (35.7)† 6 (31.6) 11 (57.9) 6 (14.6)†
17 (11.8) 50 (34.7) 43 (32.0) 38 (26.4) 34 (23.6) 89 (61.8) 11 (7.7)
0.03 0.05 0.05 0.01 0.9 0.7 0.02
19.6 (15.7)
34.2 (18.6)
46.4 (20.0)
56.1 (27.0)†
37.2 (22.6)
<0.0001
25.9%
17.2%
0.0%
0.0%†
12.5%
0.004
p-value
Patient Demographics Mean age (SD) Female sex (%) Caucasian race (%) Not married (%) Ocular Surgical History Refractive Surgery (%) Cataract Surgery (%) Medical History Fibromyalgia (%) Depression (%) Anxiety (%) Migraine (%) Rheumatologic Condition (%) Allergic Condition (%) "Bad" health status (%) OSDI Score Examination Corneal staining
Proparacaine response
N/A
70.3%
69.0%
50.0%†
67.1%
0.06
SD: standard deviation †
: p≤0.05
Unmarried subjects included those self-reported as single, divorced, or widowed. Rheumatologic conditions specifically reported included Sjögren syndrome, rheumatoid arthritis, scleroderma, mixed connective tissue disease, systemic lupus erythematosus, and sarcoidosis. Allergic conditions included allergy, hay fever, asthma, and eczema. Health status was self-reported as either “excellent”, “very good”, “good”, “reasonable”, or “bad”.
Table 2. Breakdown for patient-reported ocular pain improvement with various treatment modalities in the severe pain group.
Sunglasses Acetaminophen, non-steroidal anti-inflammatory pills Hot Compresses Artificial tears Autologous serum tears Omega-3 supplementation Opioids Steroid eye drops Ointment Lifitegrast Tetracyclines Cyclosporine A 0.05% Antidepressants Humidifier Punctal occlusion Scleral lenses Lid scrubs/wipes/baby shampoo Exercise Lyrica, Neurontin, or Gabapentin Yoga Onion goggles Acupuncture
A lot 0/14 2/15 2/13 2/19 1/8 1/9 1/7 0/12 1/15 1/5 1/5 2/11 1/11 2/11 0/6 0/3 0/10 0/10 1/12 0/7 0/3 0/4
Reported Ocular Pain Improvement Partially Not at all Never tried Response rate 9/14 5/14 4/18 64.3% 7/15 6/15 4/19 60.0% 5/13 6/13 6/19 53.8% 8/19 9/19 0/19 52.6% 3/8 4/8 11/19 50.0% 3/9 5/9 10/19 44.4% 2/7 4/7 12/19 42.9% 5/12 7/12 7/19 41.7% 5/15 9/15 4/19 40.0% 1/5 3/5 14/19 40.0% 1/5 3/5 14/19 40.0% 2/11 7/11 8/19 36.4% 3/11 7/11 8/19 36.4% 2/11 7/11 8/19 36.4% 2/6 4/6 13/19 33.3% 1/3 2/3 16/19 33.3% 3/10 7/10 9/19 30.0% 3/10 7/10 9/19 30.0% 2/12 9/12 7/19 25.0% 1/7 6/7 12/19 14.3% 0/3 3/3 16/19 0.0% 0/4 4/4 15/19 0.0%
Figure Captions:
Figure 1. Distribution of reported pain severity level in patients presenting with dry eye symptoms (n=144). Subjects were subdivided by pain severity into none (0), mild (1 - 4), moderate (5 - 7), and severe (8 - 10). Figure 2. Treatment response for the entire patient cohort. The percentage of subjects reporting complete or partial improvement in ocular pain is shown with each treatment modality surveyed. Figure 3. Treatment response to topical therapies by pain group. The percentage of subjects reporting complete or partial improvement in ocular pain with each treatment is displayed, subdivided by pain severity group. Patients who reported not trying these treatments were excluded. Groups designated with an asterisk represent statistically significant differences at p≤0.05. Figure 4. Treatment response to oral therapies by pain group. The percentage of subjects reporting complete or partial improvement in ocular pain with each treatment is displayed, subdivided by pain severity group. Patients who reported not trying these treatments were excluded. Groups designated with an asterisk represent statistically significant differences at p≤0.05. Figure 5. Treatment response to non-pharmacologic supportive therapies by pain group. The percentage of subjects reporting complete or partial improvement in ocular pain with each treatment is displayed, subdivided by pain severity group. Patients who reported not trying these treatments were excluded. Groups designated with an asterisk represent statistically significant differences at p≤0.05.
Table 1. Demographics, medical and surgical history, OSDI score, and examination findings of all subjects.
None (0) [n=27]
Mild (1-4) [n=64]
Moderate (5-7) [n=34]
Severe (8-10) [n=19]
Total [n=144]
p-value
61.1 (16.0) 22 (81.5) 18 (66.7) 13 (48.1)
58.2 (14.3) 52 (81.2) 49 (76.6) 27 (42.2)
57.9 (12.8) 32 (94.1) 22 (64.7) 18 (52.9)
53.7 (18.6)† 14 (73.7) 12 (63.2) 13 (68.4)
58.1 (14.9) 120 (83.3) 101 (70.1) 71 (49.3)
0.03 0.9 0.5 0.08
0 (0.0) 8 (29.6)
5 (7.8) 18 (28.1)
5 (14.7) 7 (20.6)
3 (15.8)† 3 (15.8)
13 (9.0) 36 (25.0)
0.03 0.2
Fibromyalgia (%)
2 (7.4)
5 (7.8)
7 (20.6)
3 (15.8)
17 (11.8)
0.03
Depression (%) Anxiety (%) Migraine (%) Rheumatologic Condition (%)
6 (22.2) 7 (28.0) 3 (7.5) 6 (22.2)
20 (31.2) 16 (25.8) 9 (28.1) 16 (25.0)
16 (47.0) 12 (36.4) 11 (36.7) 6 (17.6)
8 (42.1) 8 (57.1) 15 (35.7)† 6 (31.6)
50 (34.7) 43 (32.0) 38 (26.4) 34 (23.6)
0.05 0.05 0.01 0.9
Allergic Condition (%) "Bad" health status (%)
18 (66.6) 1 (2.5)
38 (59.4) 2 (6.3)
22 (64.7) 2 (6.6)
11 (57.9) 6 (14.6)†
89 (61.8) 11 (7.7)
0.7 0.02
19.6 (15.7)
34.2 (18.6)
46.4 (20.0)
56.1 (27.0)†
37.2 (22.6)
<0.0001
25.9% N/A
17.2% 70.3%
0.0% 69.0%
0.0%† 50.0%†
12.5% 67.1%
0.004 0.06
Patient Demographics Mean age (SD) Female sex (%) Caucasian race (%) Not married (%) Ocular Surgical History Refractive Surgery (%) Cataract Surgery (%) Medical History
OSDI Score Examination Corneal staining Proparacaine response
SD: standard deviation †
: p≤0.05
Unmarried subjects included those self-reported as single, divorced, or widowed. Rheumatologic conditions specifically reported included Sjögren syndrome, rheumatoid arthritis, scleroderma, mixed connective tissue disease, systemic lupus erythematosus, and sarcoidosis. Allergic conditions included allergy, hay fever, asthma, and eczema. Health status was self-reported as either “excellent”, “very good”, “good”, “reasonable”, or “bad”.
Table 2. Breakdown for patient-reported ocular pain improvement with various treatment modalities in the severe pain group.
Sunglasses Acetaminophen, non-steroidal anti-inflammatory pills Hot Compresses Artificial tears Autologous serum tears Omega-3 supplementation Opioids Steroid eyedrops Ointment Lifitegrast Tetracyclines Cyclosporine A 0.05% Antidepressants Humidifier Punctal occlusion Scleral lenses Lid scrubs/wipes/baby shampoo Exercise Lyrica, Neurontin, or Gabapentin Yoga Onion goggles Acupuncture
A lot 0/14 2/15 2/13 2/19 1/8 1/9 1/7 0/12 1/15 1/5 1/5 2/11 1/11 2/11 0/6 0/3 0/10 0/10 1/12 0/7 0/3 0/4
Reported Ocular Pain Improvement Partially Not at all Never tried Response rate 9/14 5/14 4/18 64.3% 7/15 6/15 4/19 60.0% 5/13 6/13 6/19 53.8% 8/19 9/19 0/19 52.6% 3/8 4/8 11/19 50.0% 3/9 5/9 10/19 44.4% 2/7 4/7 12/19 42.9% 5/12 7/12 7/19 41.7% 5/15 9/15 4/19 40.0% 1/5 3/5 14/19 40.0% 1/5 3/5 14/19 40.0% 2/11 7/11 8/19 36.4% 3/11 7/11 8/19 36.4% 2/11 7/11 8/19 36.4% 2/6 4/6 13/19 33.3% 1/3 2/3 16/19 33.3% 3/10 7/10 9/19 30.0% 3/10 7/10 9/19 30.0% 2/12 9/12 7/19 25.0% 1/7 6/7 12/19 14.3% 0/3 3/3 16/19 0.0% 0/4 4/4 15/19 0.0%