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Incomplete response to artificial tears is associated with features of neuropathic ocular pain
  1. Anat Galor1,2,
  2. Hatim Batawi1,2,
  3. Elizabeth R Felix1,3,
  4. Todd P Margolis4,
  5. Konstantinos D Sarantopoulos1,5,
  6. Eden R Martin6,7,
  7. Roy C Levitt1,5,6,7
  1. 1Department of Ophthalmology, Miami Veterans Administration Medical Center, Miami, Florida, USA
  2. 2Bascom Palmer Eye Institute, University of Miami, Miami, Florida, USA
  3. 3Department of Physical Medicine and Rehabilitation, University of Miami Miller School of Medicine, Miami, Florida, USA
  4. 4Departement of Ophthalmology, Washington University School of Medicine, St Louis, Missouri, USA
  5. 5Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, Florida, USA
  6. 6John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA
  7. 7John T Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA
  1. Correspondence to Dr Anat Galor, Miami Veterans Administration Medical Center, 1201 NW 16th Street, Miami, FL 33125, USA; agalor{at}med.miami.edu

Abstract

Aims Artificial tears are first-line therapy for patients with dry eye symptoms. It is not known, however, which patient factors associate with a positive response to therapy. The purpose of this study was to evaluate whether certain ocular and systemic findings are associated with a differential subjective response to artificial tears.

Methods Cross-sectional study of 118 individuals reporting artificial tears use (hypromellose 0.4%) to treat dry eye-associated ocular pain. An evaluation was performed to assess dry eye symptoms (via the dry eye questionnaire 5 and ocular surface disease index), ocular and systemic (non-ocular) pain complaints and ocular signs (tear osmolarity, tear breakup time, corneal staining, Schirmer testing with anaesthesia, and eyelid and meibomian gland assessment). The main outcome measures were factors associated with differential subjective response to artificial tears.

Results By self-report, 23 patients reported no improvement, 73 partial improvement and 22 complete improvement in ocular pain with artificial tears. Patients who reported no or partial improvement in pain with artificial tears reported higher levels of hot-burning ocular pain and sensitivity to wind compared with those with complete improvement. Patients were also asked to rate the intensity of systemic pain elsewhere in the body (other than the eye). Patients who reported no or incomplete improvement with artificial tears had higher systemic pain scores compared with those with complete improvement.

Conclusions Both ocular and systemic (non-ocular) pain complaints are associated with a differential subjective response to artificial tears.

  • Ocular surface
  • Epidemiology
  • Treatment Medical

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Introduction

Dry eye affects the quality of life of millions of people worldwide.1–3 The main morbidity of dry eye comes from its symptoms, which are varied and include pain, dysesthesias and visual disturbances. To address symptoms, physicians usually implement a step-ladder approach with first-line treatment being artificial tears. While many patients respond, either partially or completely, to artificial tears, it is not always possible to predict which patients will require further therapy. Undertreatment of dry eye symptoms can prolong ocular morbidity and increase the cost of therapy.4 ,5 Furthermore, in a prospective study, dry eye severity grade (composite of symptoms and signs) worsened over 12 months in patients randomised to artificial tears (32%) compared with cyclosporine (6%), suggesting that targeted treatment of inflammation in dry eye may affect its natural history.6

There is a growing understanding that many patients diagnosed with dry eye describe features of neuropathic pain, including spontaneous pain, dysesthesias (unpleasant, abnormal sensations), hyperalgesia (exaggerated pain response to suprathreshold noxious stimuli) and allodynia (pain response to normally non-noxious stimuli).7–9 In general, pain disorders can be divided into two categories: nociceptive and neuropathic, both of which are likely to be present in patients diagnosed with dry eye. Nociceptive pain is mediated by healthy sensory neurons responding to noxious stimuli, such as hyperosmolarity or air pollution. Neuropathic pain, on the other hand, occurs when there is damage and subsequent dysfunction in the somatosensory system. This dysfunction can occur due to alterations in anatomy, gene expression, signalling mechanisms or ion channel activity and manifests as reduced activation thresholds, increased excitability, enhanced synaptic transmission and abnormal signal amplification.7–9

Like some patients with dry eye, patients with neuropathic pain frequently complain of symptoms without observable signs of disease.7 In a similar manner, patients with neuropathic pain (not involving the eye) often do not respond to therapies targeting peripheral tissues.10–12 Based on the above, in this study we tested whether patients with symptoms of neuropathic ocular pain (NOP) were more likely to have an incomplete response to artificial tears than those patients without such symptoms.

Methods

Study population

Patients with otherwise healthy eyelid and corneal anatomy were prospectively recruited from the Miami VAMC eye clinic between October 2013 and April 2015 and underwent a complete ocular surface examination. Inclusion criteria included use of artificial tears (hypromellose 0.4%, Natural Balance) to treat dry eye-associated ocular pain. Exclusion criteria included contact lenses wear, history of refractive surgery, ocular medications with the exception of artificial tears, HIV, sarcoidosis, graft-versus-host disease or a collagen vascular disease, active external ocular process, cataract surgery within the last six months or a history of glaucoma or retinal surgery.

Data collected

For each individual, we collected demographic information, past ocular and medical history, and medication information. Patients filled out several standardised questionnaires including (1) dry eye severity questionnaires (dry eye questionnaire 5 (DEQ5)13 and ocular surface disease index (OSDI))14; (2) numerical rating scales (NRS) for pain intensity both in the eye and systemically (pain not involving the eye); (3) questions thought to be suggestive of NOP, specifically the presence of hot-burning ocular pain, sensitivity to light (is your eye pain provoked or increased by light?), wind (is your eye pain provoked or increased by wind?) and change in temperature (is your eye pain provoked or increased by air temperature (air conditioned/warm weather)?), all rated on a scale of 0–10; (4) depression questionnaire (patient health questionnaire); and (5) post-traumatic stress disorder (PTSD) questionnaire (PTSD Checklist—Military Version).

In addition, all patients underwent tear film assessment including (1) tear osmolarity (TearLAB, San Diego, California, USA) (once in each eye), (2) tear breakup time (5 µL fluorescein placed, three measurements taken in each eye and averaged), (3) corneal staining (NEI scale, five areas of cornea assessed),15 (4) Schirmer testing with anaesthesia and (5) eyelid and meibomian gland assessment.16 Eyelid vascularity was graded on a scale of 0–3 (0, none; 1, mild telangiectasias; 2, moderate telangiectasias; 3, severe telangiectasias) as was meibomian gland plugging (0, none; 1, less than a third of lower eyelid margin; 2, 1/3 to 2/3 of eyelid margin; 3, >2/3 of eyelid margin). Meibum quality was graded on a scale of 0–4 (0, clear; 1, cloudy; 2, granular; 3, toothpaste; 4, no meibum extracted) as was meibomian gland atrophy.17 Anatomical changes assessed included eyelid laxity and the presence of conjunctivochalasis. The presence of lower eyelid laxity was determined by the snap back test. A grade of 0 indicated laxity within normal limits, and a grade of 1 indicated a delay of 1–5 s for the lower lid to return to its native state. A grade of 2 indicated persistent separation necessitating a blink to return to the normal state. Upper eyelid laxity was determined by pulling on the forehead skin and evaluating movement of the upper eyelids. A grade of 0 indicated laxity within normal limits. A grade of 1 indicated rotation of the upper eyelid up to 50% or an elevation by 6–10 mm; a grade of 2 indicated rotation between 50% and 100% or an elevation >10 mm.18 Conjunctivochalasis was graded as absent or present in each area of the lower eyelid (temporal, central, nasal) based on the obliteration of the tear film by conjunctivae in the region of interest.

Main outcome measures

Response to artificial tears was assessed by the question, “If you use artificial tears to treat eye pain, does the treatment alleviate the pain?” Response options included not at all, somewhat and completely. The frequency and magnitude of ocular and systemic findings were then quantified by response groups.

Statistical analysis

All statistical analyses were performed using SPSS V.21.0 (SPSS, Chicago, Illinois, USA) statistical package. Frequencies and descriptive statistics were applied to the data, as appropriate. χ2 and analysis of variance tests were applied (as appropriate) to compare categorical or continuous variables between subjects. Multivariable logistic regression analysis was used to determine which factors associated with complete response to artificial tears. This sample size was deemed appropriate to detect variables with moderate effect size; with a sample size of 118 patients and response probability of 35% and α=0.05, the power was approximately 80% to demonstrate effects of variables with OR ≥3 in a logistic regression model.

Results

Study population

The mean age of the 118 study patients was 65 years (SD 11). Of these 118 patients, 23 reported no improvement to ocular pain with artificial tears, 73 patients reported partial improvement and 22 reported complete improvement. Artificial tears were used on average 2.7 times daily (SD 1.8) in those reporting no improvement, 2.6 times daily (SD 1.4) in those reporting partial improvement and 2.3 times daily (SD 1.2) in those reporting complete improvement, p=0.66. There were no significant differences in the length of time patients reported using artificial tears between the three different response groups (no improvement=mean 32 months (SD 22); partial=mean 41 months (SD 52); and complete=mean 23 months (SD 24), p=0.20).

The relationship between systemic comorbidities and response to artificial tears

We first examined the relationship between patient demographics, comorbidities and systemic medication use in the three groups of patients with different degrees of ocular pain reduction (none, partial or complete) in response to treatment with artificial tears. As summarised in table 1, we found that depression scores were higher in patients who reported no or partial improvement in ocular pain compared with those with complete improvement (p=0.047). In a similar manner, patients with either no or incomplete treatment response used anxiolytics or antihistamines more frequently compared with those patients with a complete treatment response (p<0.05).

Table 1

The relationship between population demographics, comorbidities and systemic medications with subjective response to artificial tears

The relationship between dry eye symptoms, ocular pain and systemic pain elsewhere in the body (other than the eye) and response to artificial tears

Dry eye symptom severity, as assessed by DEQ5 and OSDI, was not significantly different among the three treatment response groups (table 2). Specific ocular symptoms, however, such as the presence of hot-burning ocular pain and sensitivity to wind were significantly different among the three treatment response groups, with higher pain and sensitivity scores in those patients with no or incomplete treatment response compared with those patients with a complete treatment response (p<0.05). A similar pattern was seen with respect to systemic pain elsewhere in the body (other than in the eye), with higher mean systemic pain ratings in those with either no or incomplete treatment responses compared with those patients with a complete treatment response.

Table 2

The relationship between dry eye symptoms, ocular and systemic pain, neuropathic ocular pain (NOP) features and subjective response to artificial tears

The relationship between dry eye signs and response to artificial tears

Patients with complete subjective responses were more likely to have abnormal lid parameters (vascularity, meibum quality) compared with those with partial or no response to artificial tears (table 3). There were no other significant differences in the distribution of other ocular findings.

Table 3

The relationship between ocular signs and subjective response to artificial tears

In a forward-step multivariable model taking into account age, depression score, use of antihistamines and anxiolytics, systemic pain (average NRS over 1-week recall), symptoms of NOP (hot-burning ocular pain and sensitivity to wind) and eyelid parameters (meibum quality and eyelid vascularity), a higher systemic pain score (OR 1.35, 95% CI 1.1 to 1.6, p=0.003) was significantly associated with an incomplete self-reported treatment response to artificial tears. Abnormal meibum quality, on the other hand, was associated with a reduced risk of an incomplete treatment response (OR 0.12, 95% CI 0.03 to 0.50, p=0.004).

Discussion

The term dry eye represents a heterogeneous group of disorders, with some patients manifesting symptoms, some patients manifesting signs and some both. Furthermore, among symptoms, some patients complain of visual disturbances, others of tearing and others of pain with varied severity and persistence. Thus, an important first step in individualising management of dry eye is to identify subgroups that are more likely to benefit from one therapeutic approach than another. This paradigm has been successfully applied to dry eye signs, as patients are grouped by the presence of aqueous or evaporative deficiency, with different local treatments for each subgroup, but has not been applied to dry eye symptoms. Our study aimed to determine which clinical factors, including specific symptoms, were associated with an incomplete response to artificial tears to see whether this might aid in dry eye subgroup classification. We found that several ocular and systemic features were associated with an incomplete response to artificial tears, particularly the presence of hot-burning ocular pain and higher-intensity ratings of pain elsewhere in the body (other than the eye). Interestingly, abnormal meibomian gland parameters were associated with a better response to artificial tears.

Neuropathic pain has been well described for non-ocular sites, but it is rarely considered as an ocular diagnosis except in the context of post-herpetic neuralgia. The density and location of corneal nociceptors (integrated between superficial epithelial cells) makes them vulnerable to repeated environmental insults,19 and episodic or ongoing damage may result in altered healing, maladaptive neuroplasticity and hypersensitivity to normally non-noxious stimuli. Furthermore, corneal polymodal neurons are particularly susceptible to injury-induced sensitisation, resulting in spontaneous firing and lower stimulation thresholds after injury.20 The development of central sensitisation due to changes in second-order (and higher) afferent neurons as a result of chronic stimulation of corneal nociceptors may further explain allodynia, spatial spread of pain and a poor response to artificial tears. Importantly, central sensitisation may explain symptoms of dry eye in the absence of ocular surface pathology.

Our findings are consistent with observations by others regarding the failure of neuropathic pain states to respond to local therapies.10–12 As with all diseases, it would be beneficial for physicians treating dry eye to have useful metrics (clinic and subclinical) that predict response to treatment. We believe that the presence of self-reported symptoms of NOP may prove useful as a means to determine which patients with dry eye are more or less likely to respond to artificial tears alone. Interestingly, however, symptoms of NOP were not significant in a multivariable model, whereas intensity of pain elsewhere in the body did remain a significant factor in the model. This reinforces our previous findings that non-ocular symptoms of discomfort are important when considering patients with dry eye. In fact, we have previously shown that systemic pain intensity ratings, depression and PTSD correlate more closely with dry eye symptoms than do ocular signs.21

As with all studies, the current work has limitations that need to be considered. First, we recognise that patients’ self-reported responses on pain questionnaires are not the same as direct assays of nerve conduction. But the questionnaires that we used have been validated in systemic pain. Furthermore, studies of human corneal nerve conduction are not currently available. Second, our main outcome variable (response to artificial tears) was assessed based on subjective patient recall and not a prospective clinical trial. Third, results from our patient population, which consists of older, mostly male US veterans seeking eye care services, may not be generalisable to other dry eye populations, including female patients. Fourth, our focus was on assessment of artificial tears in attenuating ocular pain, and therefore, we cannot comment on which factors affected artificial tear efficacy in treating other dry eye-related complaints, such as blurry vision. Finally, our study did not include individuals with concomitant ocular comorbidities such as contact lens use, glaucoma, post-herpetic pain and post-photorefractive surgery. Future studies will be needed to re-evaluate whether similar factors associate with response to artificial tears in these patient populations.

Despite these limitations, we believe that our results are novel and important because they suggest that a well-established set of patient symptoms may help direct treatment decisions. For example, in patients with ocular surface disruption but no features of NOP, starting artificial tears alone is probably a reasonable approach. However, in patients who have symptoms of NOP or complain of severe systemic pain, multimodal therapy may be more appropriate, with a focus both on the ocular surface and perhaps modulating the perception of nociceptive neurons that innervate the ocular surface. Limited data are available, however, to support the use of medications typically used for neuropathic pain in the management of dry eye symptoms.22–25 Further studies are, therefore, needed to assess whether centrally acting neuromodulators have a role in patients with clinical features of NOP and dry eye-associated ocular pain.

Acknowledgments

We thank Drs D A Lubarsky and K Candiotti for their generous input and support.

References

Footnotes

  • Contributors All authors of this research paper have directly participated in the planning, execution or analysis of this study; had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis; and have read and approved the final version submitted. Research design: AG, ERF, KDS, ERM and RCL. Data acquisition: AG. Data analysis: AG, HB, TPM and ERF. Manuscript preparation: AG, HB, ERF, TPM, KDS, ERM and RCL.

  • Funding Supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Clinical Sciences Research and Development's Career Development Award CDA-2-024-10S (AG), NIH Center Core Grant P30EY014801, Research to Prevent Blindness Unrestricted Grant, Department of Defense (DOD—grant# W81XWH-09-1-0675 and grant# W81XWH-13-1-0048 ONOVA) (institutional); NIH NIDCR R01 DE022903 (RCL), and the Department of Anesthesiology, Perioperative Medicine, and Pain Management, University of Miami Miller School of Medicine, Miami, Florida, for funding.

  • Disclaimer The contents of this study do not represent the views of the Department of Veterans Affairs or the US government.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Miami VA Institution Review Board approval was obtained to allow the prospective evaluation of patients. The study was conducted in accordance with the principles of the Declaration of Helsinki.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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