Objective Studies of patients with non-ocular pain suggest that it is therapeutically useful to identify those with features of neuropathic pain. No data is available, however, on whether this approach has similar utility in dry eye. The purpose of this study was to determine whether severity and persistence of dry eye symptoms associate with self-reported symptoms of neuropathic ocular pain (NOP).
Methods Design: Cohort study. Participants/setting: 102 men seen in the Miami Veterans Affairs eye clinic. A baseline evaluation was performed consisting of the dry eye questionnaire 5 (DEQ5) and ocular surface evaluation. Patients were contacted ≥2 years later to repeat the DEQ5 and complete questionnaires that further characterised their eye pain. Main outcome measure: The relationship between dry eye symptom severity and persistence (DEQ5) and additional measures of ocular pain (NOP).
Results Of 102 patients with variable dry eye symptoms, 70 reported at least mild symptoms on both encounters (DEQ5≥6). Fifty-four of 70 (77%) reported ≥1 NOP feature, and the number of NOP features correlated moderately with dry eye symptoms at both encounters (r=0.31–0.46, p<0.01). Patients with any symptom of NOP had higher dry eye symptom scores at both encounters (p<0.05), but similar ocular surface parameters. Hypersensitivity to wind and photoallodynia were associated with having mild or greater symptoms on both encounters (OR 3.4, 95% CI 1.2 to 10.0, p=0.02; OR 15.6, 95% CI 2.0 to 123, p=0.009, respectively).
Conclusions NOP features are common in patients with symptomatic dry eye and these features correlate with symptom severity and persistence.
- Ocular surface
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Dry eye affects the quality of life of millions of Americans.1 One challenge to effectively managing dry eye is that patients given the diagnosis have a heterogeneous group of disorders. We believe that an important first step in individualising the treatment of dry eye is to classify patients with dry eye by clinical signs, and by symptoms, an approach largely not taken by eye care providers. In fact, the most commonly used dry eye questionnaires arrive at a symptom score by combining a variety of different types of symptoms, including visual disturbances, tearing and pain, rather than using these symptoms to categorise patients.2 ,3
Data from other chronic pain conditions may shed light on improved ways to classify symptoms of patients with dry eye.4 ,5 As defined by the International Association for the Study of Pain, pain is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”6 Based on this broadly accepted definition, some dry eye symptoms (eg, burning, aching) should be classified as pain.
Pain disorders are broadly classified into two categories: nociceptive pain, which is the normal physiological response to a noxious stimulus and which typically stops when the noxious stimulus terminates; and neuropathic pain, which is pain that persists in the absence of the initiating insult. Neuropathic pain is caused by a wide array of disorders of the somatosensory nervous system and includes conditions such as postherpetic neuralgia, diabetic neuropathy and phantom limb pain.7 Neuropathic pain is frequently chronic in nature.7
There is a growing understanding that many patients diagnosed with dry eye describe features of neuropathic pain, including spontaneous pain, dysaesthesias (unpleasant, abnormal sensation), hyperalgesia (exaggerated pain response to suprathreshold noxious stimuli) and allodynia (pain response to normally non-noxious stimuli).7 ,8 Furthermore, some patients diagnosed with dry eye have abnormal corneal nerve morphology and sensitivity.8–10 It is not known, however, what proportion of patients with dry eye symptoms report features of neuropathic pain, and whether these symptoms associate with disease severity. The goal of this study was to evaluate whether severity and persistence of dry eye as assayed by the dry eye questionnaire 5 (DEQ5) associated with self-reported symptoms of neuropathic ocular pain (NOP).
The study population built on a cohort of male patients previously recruited from the Miami Veterans Affairs Medical Center for a study on the relationship between dry eye symptoms and systemic androgen levels.11 This cohort consisted of 263 patients with grossly normal eyelid, conjunctival and corneal anatomy. Exclusion criteria included age under 50 years, contact lens use, recent ocular surgery (<3 months), active anterior segment ocular disease other than dry eye (eg, keratitis) or a diagnosis of HIV, sarcoidosis, graft-versus host disease or any collagen vascular disease.12 Of the original 263 patients, we were able to recontact 102 members to re-evaluate their dry eye symptoms, as part of a quality improvement project. Of the 161 that were not recontacted, 13 had died, 14 had incorrect contact information, 109 could not be reached and 25 were not interested in participating. No differences in demographic information (age, race, ethnicity) were found between participants and non-participants. Miami VA Institution Review Board approval was obtained to perform a chart review and link patient data to the questionnaires. The study was conducted in accordance with the principles of the Declaration of Helsinki.
For each individual, we collected demographic information, pertinent history and medication information from the medical record. At the initial visit, all patients completed the DEQ53 and underwent an ocular surface examination. The ocular surface examination included measurement of tear osmolarity (TearLAB, San Diego, California, USA), tear break-up time, corneal staining (Oxford (Bron)), basal tear secretion test (Schirmer's strips with anaesthesia), and morphological and qualitative characterisation of the eyelid margin and meibomian glands.12 The DEQ5 was selected because its score combines patient responses regarding discomfort, dryness and tearing without considering visual function. The more commonly used Ocular Surface Disease Index, on the other hand, considers visual function and includes questions related to difficulty with reading, driving at night, working with a computer, and watching TV. Many of our patients seek eye care treatment for visual dysfunction, and on pilot testing, many had high Ocular Surface Disease Index scores for reasons other than dry eye.
The 102 patients that we could contact were again asked to complete the DEQ5 2–3 years later, along with the short-form McGill Pain Questionnaire13 (SF-MPQ) as it pertained to their ocular symptoms. The SF-MPQ is commonly used by pain specialists to characterise features of pain.5 The questionnaire consists of 15 words which include the sensory descriptors: throbbing, shooting, stabbing, sharp, cramping, gnawing, hot burning, aching, heavy, tender, splitting; and the affective descriptors: tiring exhausting, sickening, fearful and punishing cruel quantitatively scored from 0 (none) to 3 (severe). Patients were asked to apply these descriptors to their eye pain. The SF-MPQ was scored in three ways: an overall score, generated by summing responses to all 15 descriptors; a sensory score, calculated by summing responses to the sensory descriptors (1–11); and an affective score, calculated by summing responses to the affective descriptors (12–15). In addition, each descriptor of the SF-MPQ can be examined individually. Of note, hot burning is a classic descriptor of dysaesthesia and is the SF-MPQ descriptor most closely related to neuropathic pain.5 Patients were also asked about NOP symptoms of allodynia (eye pain caused or worsened by light (photoallodynia) and/or a change in temperature) and hyperalgesia (eye pain caused or worsened by wind).
Main outcome measures
The main outcome measure was the relationship between dry eye symptom severity and persistence (DEQ5) and additional measures of ocular pain (eg, SF-MPQ scores, NOP). Features of NOP were considered present if the patient (1) characterised the eye pain as hot burning, (2) reported symptoms of allodynia to light and/or change in temperature and/or (3) reported symptoms of hyperalgesia to wind.
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 Student's t tests (for normally distributed variables), and Mann-Whitney tests (for non-normally distributed variables) were applied (as appropriate) to compare categorical and continuous variables between subjects. Multivariable logistic regression analysis was used to determine factors that correlated with persistent dry eye symptoms over 2–3 years.This sample size was deemed appropriate to detect factors with moderate effect size, such as on symptom persistence (with a sample size of 102 patients and response probability of 15% and α=0.05, the power was greater than 90% to demonstrate effects of factors with OR ≥2.0 in a multiple logistic regression model for a variety of types of variables (ie, normally distributed continuous, dichotomous, ordinal)).
The mean age of the 102 study patients was 68 years (SD 8.2) (table 1). At the first study visit 81 patients (79%) reported at least mild dry eye symptoms (DEQ5≥6). At the second encounter, a mean of 2.8 years later (SD 0.34), 70 of these 81 patients (86%) reported persistence of at least mild dry eye symptoms.
Patients with persistent dry eye symptoms frequently report ocular pain
Of the 70 patients with persistent dry eye symptoms (DEQ5≥6 on both encounters), 52 (74%) complained of 1 or more eye pain descriptors on the SF-MPQ. Of those 52, mean total SF-MPQ scores were 4.0 (SD 5.5), with a mean sensory score of 3.64 (SD 3.9) and a mean affective score of 2.8 (SD 2.9). SF-MPQ scores correlated moderately with dry eye symptoms as assayed by the DEQ5 on the second encounter: r=0.35 (total), 0.39 (sensory) and 0.26 (affective), p value <0.05 for all.
Patients with persistent dry eye symptoms frequently report clinical features of NOP
Of the 70 patients with persistent dry eye symptoms, 54 (77%) complained of one or more features of NOP; 26 (37%) of burning, 33 (47%) of hypersensitivity to wind, 26 (37%) of sensitivity to light and 17 (24%) of sensitivity to temperature. Twenty-one patients (30%) described one NOP feature, 20 (29%) described two NOP features, 8 (11%) described three NOP features and 4 (6%) described all four NOP features. The presence of any NOP feature was associated with significantly higher dry eye symptom scores at either encounter. However, signs of dry eye (tear break-up time, Schirmer scores) were similar between those with and those without symptoms of NOP (assessed at first visit) (table 2).
NOP features correlate with persistent dry eye symptoms
We next used univariable logistic regression analyses to determine whether there was any association between each symptom of NOP (ocular pain described as hot burning, hyperalgesia to wind, and allodynia to light or change in temperature) and symptoms of persistent dry eye (defined by DEQ5≥6 on both encounters) in our study group. As noted in table 3, there was a statistically significant correlation between persistent dry eye and each of the four symptoms of NOP. We next evaluated this same data using a multivariable forward stepwise logistic regression model that included patient demographics, comorbidities, clinical descriptors of NOP and ocular surface examination findings. Using this model we found a statistically significant association between persistent dry eye symptoms and hypersensitivity to wind (OR 3.4, 95% CI 1.2 to 10.0, p=0.02) and photoallodynia (OR 15.6, 95% CI 2.0 to 123, p=0.009).
This study aimed to determine whether pain and NOP, measured by metrics standardly used by pain specialists, are present in patients with persistent dry eye. First, we found that a significant proportion of patients with dry eye symptoms had ocular pain as assessed by the SF-MPQ, a well-established assay of pain. Second, a significant proportion of patients complained of features of NOP (dysaesthesia, allodynia and hyperalgesia). Furthermore, the presence of these features associated with dry eye symptom severity and persistence. These findings are important since in non-ocular sites the treatment of neuropathic pain frequently does not respond to local therapies.14
Previous studies have summarised potential insults and anatomical locations where the generation of NOP might occur.8 ,15 The rich density and superficial location of the corneal nociceptors, integrated between superficial epithelial cells, makes them vulnerable to damage and injury in the setting of even minor insults.16 Recurrent damage to these exposed nerve endings may result in altered neuronal healing, maladaptive neuroplasticity, and prolonged hypersensitivity to normally non-noxious stimuli. Confocal microscopy studies have demonstrated abnormal corneal nerve morphology (nerve sprouts, increased nerve thickness, beadlike formations, and tortuosity) in a subset of patients diagnosed with dry eye.9 ,17–21 Furthermore, corneal polymodal neurons easily sensitise after injury, displaying spontaneous firing, lower thresholds and increased responses to stimuli.22 However, neuroplasticity associated with dry eye is likely to occur not solely at the corneal surface.8 Corneal nociceptors have their cell bodies in the trigeminal ganglion and synapse in the brainstem trigeminal nuclei, specifically the trigeminal subnucleus interpolaris/subnucleus caudalis (Vi/Vc) transition zone and the subnucleus caudalis/upper cervical transition zone (Vc/C1–2).23 ,24 Dry-responsive second order neurons have been identified in the Vi/Vc zone, and a subset of these neurons also receive input from corneal afferents sensitive to acidity, heat and chemicals.24 Therefore, neurons in the transition zone appear to integrate innocuous as well as noxious sensory information from the eye, and may constitute the neurophysiological substrate of central sensitisation.25
Despite evidence that neuropathic pain may be driving dry eye symptoms in some patients with dry eye, limited data are available to support the use of neuropathic pain medication in the management of dry eye. For example, diclofenac, in addition to its antiprostaglandin effects, attenuates excitatory neurotransmitter release, resulting in an antiallodynic and antihyperalgesic effect.16 ,26–28 In one study, treatment of healthy volunteers with diclofenac drops (Voltaren, Novartis) attenuated ocular discomfort to mechanical, chemical and thermal stimuli.29 On the other hand, treatment with topical flurbiprofen, a non-steroidal anti-inflammatory agent without similar effects on neurotransmitter release, did not attenuate discomfort in the same study.
As with all studies, the current work has limitations that need to be considered. First, we recognise that patients’ self-reported responses to any questionnaire, including the SF-MPQ, cannot definitely diagnose the presence of neuropathic pain, which requires direct assays of nerve conduction. But the questionnaires that we used have been validated in non-ocular pain and direct studies of human corneal nerve conduction are not currently available. Second, results from our patient population, which consists of older male US veterans seeking eye care services, may not be generalisable to other dry eye populations, including female patients. Third, dry eye symptom persistence was defined by two time points in our study, and this definition may not adequately capture the distinction between patients with transient versus persistent symptoms. Finally, the SF-MPQ pain descriptors are general descriptors and as such, do not incorporate many of the specific complaints of patients with dry eye.
Despite these limitations, these data are important because they suggest patient symptoms may affect treatment decisions. For example, in patients with ocular surface disruption but no features of NOP, optimising the ocular surface environment is a reasonable approach. In patients who display features of NOP, however, multimodal therapy may be more appropriate, with a focus on ocular surface protection and on modulating ocular sensory apparatus function. Further studies are needed to assess whether topical and/or centrally acting neuromodulators have a role in the treatment of patients with dry eye with features of NOP.
The authors thank Drs D A Lubarsky and K Candiotti for their generous input and support. The authors note that the contents of this study do not represent the views of the Department of Veterans Affairs or the US Government.
Contributors All authors contributed to this manuscript: design and conduct of the study (AG, LZ, ERF, KDS and RCL) collection (AG) management (AG) analysis (AG and WF) Interpretation of the data (AG, ERF, WF, RCL and TPM) preparation (AG, SDW and RCL) review or approval of the manuscript (AG, LZ, SDW, ERF, WF, ERM, KDS, RCL and TPM).
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 ERM), and the Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, Florida for funding.
Competing interests None.
Ethics approval Miami VAMC IRB.
Provenance and peer review Not commissioned; externally peer reviewed.
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