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Neuropathic Ocular Pain due to Dry Eye Is Associated With Multiple Comorbid Chronic Pain Syndromes

  • Anat Galor
    Affiliations
    Miami Veterans Administration Medical Center, Miami, Florida

    Bascom Palmer Eye Institute, University of Miami, Miami, Florida
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  • Derek Covington
    Affiliations
    Miami Veterans Administration Medical Center, Miami, Florida

    Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, Florida
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  • Alexandra E. Levitt
    Affiliations
    Bascom Palmer Eye Institute, University of Miami, Miami, Florida
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  • Katherine T. McManus
    Affiliations
    Miami Veterans Administration Medical Center, Miami, Florida

    Bascom Palmer Eye Institute, University of Miami, Miami, Florida
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  • Benjamin Seiden
    Affiliations
    Bascom Palmer Eye Institute, University of Miami, Miami, Florida
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  • Elizabeth R. Felix
    Affiliations
    Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, Florida

    Department of Physical Medicine and Rehabilitation, University of Miami Miller School of Medicine, Miami, Florida
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  • Jerry Kalangara
    Affiliations
    Miami Veterans Administration Medical Center, Miami, Florida

    Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, Florida
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  • William Feuer
    Affiliations
    Bascom Palmer Eye Institute, University of Miami, Miami, Florida
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  • Dennis J. Patin
    Affiliations
    Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, Florida
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  • Eden R. Martin
    Affiliations
    John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida

    John T Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida
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  • Konstantinos D. Sarantopoulos
    Affiliations
    Miami Veterans Administration Medical Center, Miami, Florida

    Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, Florida
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  • Roy C. Levitt
    Correspondence
    Address reprint requests to Roy C. Levitt, MD, 1600 NW 10th Avenue, Miami, FL 33136.
    Affiliations
    Miami Veterans Administration Medical Center, Miami, Florida

    Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine, Miami, Florida

    John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida

    John T Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida
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Published:November 19, 2015DOI:https://doi.org/10.1016/j.jpain.2015.10.019

      Highlights

      • Dry eye (DE) exams should include an evaluation of neuropathic ocular pain (NOP).
      • DE patients with more chronic pain syndromes (high CPS group) reported NOP.
      • The high CPS group reported worse DE, depression, quality of life, and ocular and non-ocular pain.
      • NOP may share causal genetic factors with other overlapping chronic pain conditions.
      • Multidisciplinary chronic pain treatment may also benefit DE patients with NOP.

      Abstract

      Recent data show that dry eye (DE) susceptibility and other chronic pain syndromes (CPS) such as chronic widespread pain, irritable bowel syndrome, and pelvic pain, might share common heritable factors. Previously, we showed that DE patients described more severe symptoms and tended to report features of neuropathic ocular pain (NOP). We hypothesized that patients with a greater number of CPS would have a different DE phenotype compared with those with fewer CPS. We recruited a cohort of 154 DE patients from the Miami Veterans Affairs Hospital and defined high and low CPS groups using cluster analysis. In addition to worse nonocular pain complaints and higher post-traumatic stress disorder and depression scores (P < .01), we found that the high CPS group reported more severe neuropathic type DE symptoms compared with the low CPS group, including worse ocular pain assessed via 3 different pain scales (P < .05), with similar objective corneal DE signs. To our knowledge, this was the first study to show that DE patients who manifest a greater number of comorbid CPS reported more severe DE symptoms and features of NOP. These findings provided further evidence that NOP might represent a central pain disorder, and that shared mechanistic factors might underlie vulnerability to some forms of DE and other comorbid CPS.

      Perspective

      DE patients reported more frequent CPS (high CPS group) and reported worse DE symptoms and ocular and nonocular pain scores. The high CPS group reported symptoms of NOP that share causal genetic factors with comorbid CPS. These results imply that an NOP evaluation and treatment should be considered for DE patients.

      Key words

      According to the Institute of Medicine Report on chronic pain in America, chronic pain conditions affect at least 116 million US adults at a cost of $560 to $635 billion annually in direct medical treatment and lost productivity.
      Institute of Medicine (US) Committee on Advancing Pain Research, Care, and Education
      Relieving Pain in America, A Blueprint for Transforming Prevention, Care, Education and Research.
      The Institute of Medicine report further concluded that, “Chronic pain has a distinct pathology, causing changes throughout the nervous system that often worsen over time.” Individuals who suffer from one form of chronic pain often have other chronic pain conditions. These individuals will often describe mood disorders, disrupted sleep, decreased energy, difficulty concentrating, and report an overall decrease in their enjoyment of life.
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      • Williams F.M.
      Shared genetic factors underlie chronic pain syndromes.
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      Central pain syndromes.
      The phenomenon of “chronic pain syndromes” (CPS) is somewhat poorly defined, but is essentially considered to be the persistence of pain past the point at which resolution might reasonably be expected (often defined as ≥6 months). Such syndromes are thought to include functional disorders such as fibromyalgia, irritable bowel syndrome, temporomandibular pain, complex regional pain syndrome and chronic pelvic pain, as well as structural conditions such as diabetic neuropathy, osteoarthritis, and cancer pain, among others.
      Dry eye (DE) is a common disorder that affects the quality of life of millions worldwide.
      The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the International Dry Eye WorkShop (2007).
      DE is characterized by symptoms of ocular discomfort and visual disturbances, as well as variable signs including tear film and ocular surface disruption and inflammatory changes.
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      Damage or dysfunction in the corneal somatosensory pathway has also been postulated as a component of DE in some patients because of the high density and superficial location of the corneal nociceptors, which makes them vulnerable to repeated damage and injury.
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      • Levitt R.C.
      Dry eye symptom severity and persistence are associated with symptoms of neuropathic pain.
      The abnormal corneal nerve morphology and sensitivity described in some patients with DE symptoms is consistent with this mechanism.
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      Decreased corneal sensitivity in patients with dry eye.
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      The corneal pain system. Part I: The missing piece of the dry eye puzzle.
      We previously reported that a subset of DE patients described their symptoms in terms consistent with neuropathic pain, including features of evoked pain to wind and temperature as well as increased sensitivity to light (photoallodynia or photophobia).
      • Galor A.
      • Zlotcavitch L.
      • Walter S.D.
      • Felix E.R.
      • Feuer W.
      • Martin E.R.
      • Margolis T.P.
      • Sarantopoulos K.D.
      • Levitt R.C.
      Dry eye symptom severity and persistence are associated with symptoms of neuropathic pain.
      In addition to DE symptoms of a specific neuropathic quality, the symptoms described by these patients also tended to be more severe and persistent than those of their “traditional” DE counterparts.
      • Galor A.
      • Zlotcavitch L.
      • Walter S.D.
      • Felix E.R.
      • Feuer W.
      • Martin E.R.
      • Margolis T.P.
      • Sarantopoulos K.D.
      • Levitt R.C.
      Dry eye symptom severity and persistence are associated with symptoms of neuropathic pain.
      Furthermore, these symptoms were reported in the absence of objective ocular surface defects, and were more closely aligned to nonocular or central neurologic mechanisms rather than to the presence of any ongoing peripheral pathology.
      • Galor A.
      • Felix E.R.
      • Feuer W.
      • Shalabi N.
      • Martin E.R.
      • Margolis T.P.
      • Sarantopoulos C.D.
      • Levitt R.C.
      Dry eye symptoms align more closely to non-ocular conditions than to tear film parameters.
      Additional evidence that some forms of DE represent a central disorder comes from work that showed increased forearm sensitivity to heat pain during objective quantitative sensory testing in DE patients.
      • Staud R.
      Abnormal endogenous pain modulation is a shared characteristic of many chronic pain conditions.
      • Vehof J.
      • Kozareva D.
      • Hysi P.G.
      • Harris J.
      • Nessa A.
      • Williams F.K.
      • Bennett D.L.
      • McMahon S.B.
      • Fahy S.J.
      • Direk K.
      • Spector T.D.
      • Hammond C.J.
      Relationship between dry eye symptoms and pain sensitivity.
      Similar to other CPS, DE is also strongly associated with depression, post-traumatic stress disorder, and sleep disruption.
      • Finan P.H.
      • Smith M.T.
      The comorbidity of insomnia, chronic pain, and depression: Dopamine as a putative mechanism.
      • Galor A.
      • Feuer W.
      • Lee D.J.
      • Florez H.
      • Faler A.L.
      • Zann K.L.
      • Perez V.L.
      Depression, post-traumatic stress disorder, and dry eye syndrome: A study utilizing the national United States Veterans Affairs administrative database.
      • Li M.
      • Gong L.
      • Sun X.
      • Chapin W.J.
      Anxiety and depression in patients with dry eye syndrome.
      Recent evidence suggests that somatic and structural comorbid CPS, including DE, might share common genetic mechanistic factors.
      • Malkin I.
      • Williams F.M.
      • LaChance G.
      • Spector T.
      • MacGregor A.J.
      • Livshits G.
      Low back and common widespread pain share common genetic determinants.
      • Vehof J.
      • Zavos H.M.
      • Lachance G.
      • Hammond C.J.
      • Williams F.M.
      Shared genetic factors underlie chronic pain syndromes.
      Collectively, these findings suggest that in at least some individuals, DE might actually represent a chronic neuropathic pain syndrome.
      Because of these results, in this study we hypothesized that DE patients with a greater number of chronic comorbid structural and functional pain syndromes (high CPS group) would show a different phenotype than those with fewer comorbid conditions (low CPS group). To study this question, we used cluster analysis to divide our population of symptomatic DE patients into these 2 groups according to their pain complaints. We then evaluated whether the high CPS group of DE patients reported symptoms of neuropathic ocular pain compared with the low CPS group of DE patients.

      Methods

      Population Sample

      A cohort of 154 patients with DE symptoms, and a Dry Eye Questionnaire 5 (DEQ5) score ≥6 and normal eyelid and corneal anatomy were prospectively recruited from the Miami Veterans Affairs Healthcare System eye clinic between October 2013 and March 2015 and underwent a complete ocular surface examination. Patients were excluded from participation if they wore contact lenses, had ever undergone refractive, retinal, or glaucoma surgery, or had undergone cataract surgery within the past 6 months, used ocular medications with the exception of artificial tears, had a history of HIV infection, sarcoidosis, graft versus host disease, a collagen vascular disease, or acute ocular process such as conjunctivitis, infection, and iritis. The Miami Veterans Affairs institutional review board approval was granted (number 3011.02) to allow the prospective evaluation of patients after informed consent was obtained. The study was conducted in accordance with the principles of the Declaration of Helsinki and Declaration of the World Medical Association.

      Data Collection

      For each individual, we collected data on demographic characteristics, ocular and medical history, and current medications.

      Binary CPS Phenotype Determination

      Patients were asked about the presence of the following chronic pain conditions, defined as any of the following for >3 months duration: arthritis, burn pain, headaches, diabetic neuropathy, tendonitis, central pain syndrome, muscle pain, complex regional pain syndrome and/or causalgia, back pain, cancer pain, trigeminal neuralgia, sciatica, shingles, surgical pain, temporomandibular pain, and fibromyalgia. Patients were also given a pain drawing in which they marked current locations of pain. The total number of pain locations was computed from these drawings as a summary score. Using a 2-step cluster analysis on the basis of number of reported chronic pain conditions and the pain locations summary score, the patient population was divided into 2 groups. Cluster group 1 (n = 57) had a lower number of CPS (mean = 2.5, SD = 1.5) and a lower number of current pain locations (mean = 1.1, SD = .7). Cluster group 2 (n = 97) had a higher number of CPS (mean = 6.2, SD = 3.5) and a higher number of current pain locations (mean = 3.8, SD = 1.1). The remaining analyses were performed to evaluate differences in DE status between these high and low CPS cluster groups.

      Ocular Surface Evaluation

      All patients underwent a tear film assessment which included, in the order performed: 1) tear osmolarity (TearLAB, San Diego, CA), 2) tear breakup time, 3) corneal staining, 4) Schirmer strips with anesthesia, and 5) meibomian gland assessment. Tear osmolarity testing was performed once in each eye before instillation of eye drops. The osmolarity handpiece was held over the outer third of the inferior conjunctivae to sample the inferior tear meniscus. Patients were asked to look up and nasally. Tear breakup time was measured using a slit lamp biomicroscope with a cobalt blue filter and a beam approximately 4 mm wide and 10 mm high using the lowest level of illumination. Starting with the right eye, the patient looked down and nasally. The examiner gently retracted the upper lid and 5 μL of preservative-free fluorescein was placed on the superior bulbar conjunctivae. The upper lid was released and the subject was allowed to blink normally for 15 seconds. The patient's head was positioned in the headrest of the slit lamp instrument, ensuring the patient was comfortably supported with their forehead in full contact with the headrest band. The patient was instructed to blink 3 times naturally, then stare and not blink. The investigator monitored the integrity of the tear film and, using a stopwatch, measured the time from the last blink until 1 or more black (dry) spots appeared in the precorneal tear film. After the first measurement, the patient was instructed to blink naturally 3 additional times and a second measurement was taken. The procedure was then repeated a third time. After a 60-second rest period, the entire procedure was repeated for the left eye. Corneal staining was assessed using the National Eye Institute standard scoring scale to assess 5 areas of the cornea. A grade was assigned to each section of the cornea (range = 0–3) and a total score was generated by summing the 5 section scores.
      Methodologies to diagnose and monitor dry eye disease: Report of the Diagnostic Methodology Subcommittee of the International Dry Eye WorkShop (2007).
      After placement of 10 μL proparacaine in each eye, Schirmer strips were placed in the outer third of the lower conjunctivae and the length of wetting after 5 minutes was recorded in each eye. Meibomian gland assessment included an evaluation of lower eyelid vascularity, graded on a scale of 0 to 4 (0 = none; 1 = mild engorgement; 2 = moderate engorgement; 3 = severe engorgement) and meibum quality (0 = clear; 1 = cloudy; 2 = granular; 3 = toothpaste; 4 = no meibum extracted).

      Characterization of Pain Syndromes

      The following questionnaires were used to quantify the severity and characteristics of self-reported ocular and nonocular pain, mental health, and quality of life.

      Nonocular pain severity

      A numerical rating scale (NRS) questionnaire was used to assess concurrent nonocular pain.
      • Ferreira-Valente M.A.
      • Pais-Ribeiro J.L.
      • Jensen M.P.
      Validity of four pain intensity rating scales.
      Scores ranged from 0 to 10 for the following questions: 1) How would you describe the overall intensity of your pain, on average during the past week? 2) How would you describe the overall intensity of your pain when it was at its worst, during the past 1 week?

      Ocular symptoms

      Patients were instructed to complete the following standardized questionnaires regarding their ocular complaints only: 1) DEQ5 (score range = 0–22); 2) Ocular Surface Disease Index (score range = 0–100); 3) NRS questionnaire adapted for ocular pain (“How would you describe the overall intensity of your pain, on average during the past week? How would you describe the overall intensity of your pain when it was at its worst, during the past 1 week?”; score range = 0–10 for each question); 4) Neuropathic Pain Symptom Inventory applied to eye pain (NPSI) (score range = 0–100). In our modified version of the NPSI for neuropathic ocular pain we replaced 3 original descriptors (allodynia and hyperalgesia caused by brushing, pressure, or cold on the skin), with descriptors of ocular allodynia (eye pain caused or worsened by light and/or change in temperature) and ocular hyperalgesia (eye pain caused or worsened by wind); and 5) short form McGill Pain Questionnaire (sf-MPQ; score range = 0–45) to characterize eye pain (sensory and affective descriptors).

      Mental health

      Patients filled out standardized questionnaires to assess for the presence of depression using the Patient Health Questionnaire 9 (score range = 0–27) and post-traumatic stress disorder (PTSD) using the PTSD checklist-Military Version (score range = 17–85).

      Quality of life

      The Short Form Health Survey (SF-12) was used to obtain physical and mental health composite scores (score range = 0–100).

      Analysis

      Main Outcome Measures

      The main outcome measures were the frequency and severity of DE signs and symptoms (including neuropathic ocular pain), mental health indices, and quality of life measurements in the high versus the low CPS groups.

      Statistical Methods

      All statistical analyses were performed using SPSS 22.0 statistical package (SPSS Inc, Chicago, IL). Frequencies and descriptive statistics were applied to the data, as appropriate. χ2, Fisher exact, Student 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.

      Results

      Demographic Characteristics of the Population Sample

      Of the 149 subjects included in the study, 97 subjects were assigned to the high CPS group and 57 to the low CPS group on the basis of cluster analysis. The high CPS group of DE patients were younger compared with the low CPS group (Table 1). Patients in the high CPS group also more frequently reported antidepressant and analgesic medication use than their low CPS counterparts.
      Table 1Demographic Characteristics of the Population Sample
      CharacteristicsHigh CPS Group (N = 97)
      Determined using cluster analysis.
      Low CPS Group (N = 57)
      Determined using cluster analysis.
      P
      Demograhic data
       Mean age (SD)62 (11)66 (11).03
       Male sex, n (%)88 (91)52 (91).92
       White race, n (%)43 (44)32 (56).34
       Hispanic ethnicity, n (%)32 (33)11 (19).07
      Comorbidities, n (%)
       Hypertension70 (72)45 (79).35
       Diabetes mellitus38 (39)19 (33).47
       Sleep apnea23 (24)10 (18).37
       BPH15 (16)11 (19).54
      Medications, n (%)
       Anxiolytic46 (47)19 (33).09
       Antidepressant53 (55)14 (25)< .0005
       Anti-histamine22 (23)7 (12).11
       Analgesics75 (77)27 (47)< .0005
      Abbreviation: BPH, benign prostatic hypertrophy.
      NOTE. Boldface indicates statistical significance (P < .05).
      Determined using cluster analysis.

      Nonocular Pain According to Group

      Nonocular pain was rated significantly greater in the high CPS versus the low CPS group for mean and worst pain intensity during the past week (P < .0005; Table 2). Of the pain conditions reported, all were more frequent in the high CPS versus the low CPS group (Table 3). This difference was not significant for fibromyalgia, postherpetic neuralgia, and cancer pain. The overall frequency of these CPS was also low (<10%), possibly because of our predominately male sample.
      Table 2Nonocular Pain Severity (According to the NRS) in the Population Sample
      Pain SeverityHigh CPS Group (N = 97)
      Determined using cluster analysis.
      Low CPS Group (N = 57)
      Determined using cluster analysis.
      P
      Nonocular pain intensity, averaged over the past wk (0–10)6.0 (2.4)3.9 (2.9)< .00005
      Nonocular pain intensity, worst during past wk (0–10)7.0 (2.4)4.6 (3.4)< .00005
      NOTE. Data are presented as mean (SD). Boldface indicates statistical significance (P < .05).
      Determined using cluster analysis.
      Table 3Frequency of Comorbid Chronic Pain Conditions
      Classification from Yunus68.
      in the Population Sample
      ConditionHigh CPS Group (N = 97)
      Determined using cluster analysis.
      Low CPS Group (N = 57)
      Determined using cluster analysis.
      P
      Primary central sensitization
       Back pain81 (84)29 (51)< .0005
       Muscle pain71 (73)18 (32)< .0005
       Headaches52 (54)20 (35).03
       Tendonitis39 (40)7 (12)< .0005
       Central pain syndrome16 (17)0 (0).001
       Trigeminal neuralgia11 (11)0 (0).007
       TMD pain9 (9)0 (0).03
       Fibromyalgia1 (1)0 (0)1.00
      Secondary central sensitization
       Arthritis79 (81)22 (39)< .0005
       Chronic postsurgical pain33 (34)5 (9)< .0005
       Diabetic neuropathy29 (30)8 (14).03
       Sciatica33 (34)4 (7)< .0005
       Burn pain26 (27)5 (9).007
       Postherpetic neuralgia11 (11)5 (9).61
       Cancer pain4 (4)0 (0).30
      Individual central sensitivity
       CRPS/Causalgia16 (17)0 (0).001
      Abbreviations: TMD, temporomandibular joint disorder; CRPS, complex regional pain syndrome.
      NOTE. Data are presented as n (%). Boldface indicates statistical significance (P < .05).
      Classification from Yunus
      • Yunus M.B.
      Editorial review: An update on central sensitivity syndromes and the issues of nosology and psychobiology.
      .
      Determined using cluster analysis.

      Ocular Examination According to Group

      Between the high CPS and low CPS group, no significant differences were seen in any objective ocular surface metric (Table 4).
      Table 4Ocular Surface Examination in the Population Sample
      VariableHigh CPS Group (N = 97)
      Determined using cluster analysis.
      Low CPS Group (N = 57)
      Determined using cluster analysis.
      P
      Tear osmolarity, mOsm/L305 (17)303 (17).63
      Tear film breakup time (less time indicates more rapid tear evaporation), s8.9 (3.8)9.4 (3.6).39
      Corneal staining (scale of 0–15; higher value indicates more surface disruption)2.2 (2.8)2.2 (2.3).85
      Schirmer test (lower value indicates lower tear production), mm of moisture13.8 (6.6)14.0 (6.2).87
      Eye lid vascularity (scale of 0–3; higher value indicates more abnormal vascularity)0.57 (0.71)0.79 (0.84).10
      Meibum quality (scale of 0–4; higher value indicates more abnormal meibum)2.0 (1.2)1.8 (1.2).47
      NOTE. Data are presented as mean (SD). All numbers represent the more severe value in either eye.
      Determined using cluster analysis.

      Ocular Pain According to Group

      The magnitude of all DE and ocular pain symptoms was greater in the high CPS versus the low CPS group (Table 5). DE symptom scores were greater according to the DEQ5 and Ocular Surface Disease Index; and ocular pain scores were greater using all 3 instruments (NRS, NPSI, sf-MPQ; P < .05 for all). Furthermore, patients in the high CPS versus the low CPS group had significantly higher NPSI subscores for ocular burning spontaneous pain, pressing spontaneous pain, evoked pain, and paresthesias and/or dysesthesias.
      Table 5DE and Ocular Pain Symptoms in the Population Sample
      Symptom (Scale)High CPS Group (N = 97)
      Determined using cluster analysis.
      Low CPS Group (N = 57)
      Determined using cluster analysis.
      P
      DEQ5 (0–22)13.6 (3.7)11.7 (3.9).004
      OSDI (0–100)44 (25)29 (22)< .0005
      Ocular pain intensity, averaged over past wk (0–10)4.5 (2.5)2.9 (2.4)< .0005
      Ocular pain intensity, worst during past wk (0–10)5.5 (3.0)3.9 (3.0).002
      NPSI total (0–100)29 (23)19 (19).006
      NPSI subscale 1; burning spontaneous pain (0-10)3.7 (3.2)2.7 (3.0).047
      NPSI subscale 2; pressing spontaneous pain (0–10)2.8 (2.7)1.9 (2.6).03
      NPSI subscale 3; paroxysmal pain (0–10)1.9 (2.6)1.5 (2.2).34
      NPSI subscale 4; evoked pain (0–10)3.5 (2.9)2.1 (2.4).003
      NPSI subscale 5; paresthesia/dysesthesia (0–10)2.6 (2.8)1.6 (2.3).01
      sf-MPQ sensory (0–33)7.7 (7.3)4.1 (5.0).001
      sf-MPQ affective (0–12)2.8 (3.0)1.3 (1.9).01
      sf-MPQ total (0–45)10.4 (9.7)5.5 (6.6).001
      Abbreviation: OSDI, Ocular Surface Disease Index questionnaire.
      NOTE. Data are presented as mean (SD). Boldface indicates statistical significance (P < .05).
      Determined using cluster analysis.

      Mental Health and Quality of Life According to Group

      Consistent with our hypothesis, psychiatric and quality of life measurements indicated significantly worse disease scores in the high CPS group compared with the low CPS group (Table 6). Specifically, the high CPS group reported greater PTSD scores on the PTSD checklist-Military Version, greater depression scores on the Patient Health Questionnaire 9, and lower SF-12 physical and mental composite scores compared with the low CPS group (P < .01 for all).
      Table 6Psychiatric Complaints and Quality of Life in the Population Sample
      Instrument (Scale)High CPS Group (N = 97)
      Determined using cluster analysis.
      Low CPS Group (N = 57)
      Determined using cluster analysis.
      P
      PTSD checklist, military version (17–85)45 (20)36 (19).005
      Depression score via PHQ9 (0–27)10.8 (8.0)6.9 (7.5).004
      SF-12, physical composite score (0–100)35 (11)47 (10)< .0005
      SF-12, mental composite score (0–100)43 (14)48 (12).01
      Abbreviation: PHQ9, Patient Health questionnaire.
      NOTE. Data are presented as mean (SD). Boldface indicates statistical significance (P < .05).
      Determined using cluster analysis.

      Conclusions

      Neuropathic Ocular Pain Is Associated With Comorbid CPS

      The diagnosis of DE is applied to a heterogeneous collection of clinical syndromes characterized by ocular irritation and visual disturbance, often described in terms of a “foreign body sensation” or “dryness.” However, some commonly reported features of a DE type of discomfort parallel the symptoms characteristic of neuropathic pain commonly seen in CPS, including allodynia (in the case of the eye, seen in response to innocuous saline eye drops or light), hyperalgesia, burning, and pain evoked by touch, heat, or cold (as well as wind, in the case of the eye).
      • Bouhassira D.
      • Attal N.
      • Alchaar H.
      • Boureau F.
      • Brochet B.
      • Bruxelle J.
      • Cunin G.
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      • Ginies P.
      • Grun-Overdyking A.
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      • Laurent B.
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      Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4).
      • Toda I.
      • Asano-Kato N.
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      • Tsubota K.
      Laser-assisted in situ keratomileusis for patients with dry eye.
      In addition, some patients with DE also develop secondary hyperalgesia within the distribution of the trigeminal nerve, consistent with altered central pain processing.
      • Costigan M.
      • Scholz J.
      • Woolf C.J.
      Neuropathic pain: A maladaptive response of the nervous system to damage.
      This secondary hyperalgesia can present as headache, blepharospasm, or generalized discomfort around the orbit, face, and jaw.
      • Borsook D.
      • Rosenthal P.
      Chronic (neuropathic) corneal pain and blepharospasm: Five case reports.
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      • Castro A.
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      • Keller A.
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      Transition to persistent orofacial pain after nerve injury involves supraspinal serotonin mechanisms.
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      • Suzuki I.
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      • Honda K.
      • Shimizu N.
      • Sessle B.J.
      • Iwata K.
      Organization of hyperactive microglial cells in trigeminal spinal subnucleus caudalis and upper cervical spinal cord associated with orofacial neuropathic pain.
      In addition to these qualitative similarities in the character of the pain experienced in DE and other CPS, there is a growing body of literature that describes 1) that DE tends to be comorbid with other CPS, and 2) that CPS and DE appear to share common underlying genetic mechanisms, which might explain this clustering.
      Our results provide evidence for the existence of a subset of DE patients whose ocular symptoms might be the manifestation of an underlying central pain processing disorder. Patients of the high CPS group reliably described elements of neuropathic ocular pain, including paresthesias and evoked pain on NPSI scores, and more severe symptoms than the low CPS group, who we might consider to have “traditional” DE. These differences in pain quality and severity are noted without any significant differences in objective corneal pathology, again suggestive of a central disorder. In addition to DE symptomatology, we found that our high and low CPS groups also differed significantly in psychiatric indices and quality of life assessments, including significantly greater depression and PTSD scores, and lower SF-12 scores in the high CPS group. Furthermore, those in the high CPS group reported significantly higher sf-MPQ sensory and affective subscores, as well as total sf-MPQ scores. This is not surprising because of the known strong association between chronic structural and functional pain disorders and these psychiatric measures and quality of life indices.
      • Aaron L.A.
      • Burke M.M.
      • Buchwald D.
      Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder.
      • Finan P.H.
      • Smith M.T.
      The comorbidity of insomnia, chronic pain, and depression: Dopamine as a putative mechanism.
      • Klauenberg S.
      • Maier C.
      • Assion H.J.
      • Hoffmann A.
      • Krumova E.K.
      • Magerl W.
      • Scherens A.
      • Treede R.D.
      • Juckel G.
      Depression and changed pain perception: Hints for a central disinhibition mechanism.
      • Munzenmaier D.H.
      • Wilentz J.
      • Cowley Jr., A.W.
      Genetic, epigenetic, and mechanistic studies of temporomandibular disorders and overlapping pain conditions.

      Neuropathic Ocular Pain Might Represent a Central Sensitivity Syndrome

      Although the comorbid tendencies of CPS (including DE) and common underlying heritable factors have been well described, the proposed mechanism for the diverse manifestations of what appears to be a central disorder remains an open question. Although there is increasing recognition that dysregulation of central neurocircutry contributes to a range of chronic comorbid functional and structural pain disorders, the specific mechanisms remain elusive. Recently, there has been a move toward conceptualization of some of these comorbid chronic pain disorders as “central sensitivity syndromes,”
      • Finan P.H.
      • Smith M.T.
      The comorbidity of insomnia, chronic pain, and depression: Dopamine as a putative mechanism.
      • Munzenmaier D.H.
      • Wilentz J.
      • Cowley Jr., A.W.
      Genetic, epigenetic, and mechanistic studies of temporomandibular disorders and overlapping pain conditions.
      • Neblett R.
      • Hartzell M.M.
      • Cohen H.
      • Mayer T.G.
      • Williams M.
      • Choi Y.
      • Gatchel R.J.
      Ability of the central sensitization inventory to identify central sensitivity syndromes in an outpatient chronic pain sample.
      • Staud R.
      Abnormal endogenous pain modulation is a shared characteristic of many chronic pain conditions.
      • Vehof J.
      • Zavos H.M.
      • Lachance G.
      • Hammond C.J.
      • Williams F.M.
      Shared genetic factors underlie chronic pain syndromes.
      • Wasner G.
      Central pain syndromes.
      characterized by central nervous system neuroplasticity which results in increased resposiveness of nocipceptive neurons and altered descending pain modulation.
      • Costigan M.
      • Scholz J.
      • Woolf C.J.
      Neuropathic pain: A maladaptive response of the nervous system to damage.
      Central sensitivity has been postulated to underlie a variety of commonly comorbid conditions, including the structural and functional CPS assessed in this study, such as osteoarthritis, burn pain, headache, diabetic neuropathy, tendonitis, central pain syndrome, muscle pain, complex regional pain syndrome and/or causalgia, back pain, cancer pain, trigeminal neuralgia, sciatica, shingles, surgical pain, temporomandibular pain, and fibromyalgia.
      • Curatolo M.
      • Arendt-Nielsen L.
      • Petersen-Felix S.
      Central hypersensitivity in chronic pain: Mechanisms and clinical implications.
      • Dahrouge S.
      • Muldoon L.
      • Ward N.
      • Hogg W.
      • Russell G.
      • Taylor-Sussex R.
      Roles of nurse practitioners and family physicians in community health centres.
      • Finan P.H.
      • Smith M.T.
      The comorbidity of insomnia, chronic pain, and depression: Dopamine as a putative mechanism.
      • Hampson J.P.
      • Reed B.D.
      • Clauw D.J.
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      Augmented central pain processing in vulvodynia.
      • Kindler L.L.
      • Bennett R.M.
      • Jones K.D.
      Central sensitivity syndromes: Mounting pathophysiologic evidence to link fibromyalgia with other common chronic pain disorders.
      • Kindler L.L.
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      • Bennett R.M.
      Risk factors predicting the development of widespread pain from chronic back or neck pain.
      • King C.D.
      • Wong F.
      • Currie T.
      • Mauderli A.P.
      • Fillingim R.B.
      • Riley 3rd, J.L.
      Deficiency in endogenous modulation of prolonged heat pain in patients with irritable bowel syndrome and temporomandibular disorder.
      • Klauenberg S.
      • Maier C.
      • Assion H.J.
      • Hoffmann A.
      • Krumova E.K.
      • Magerl W.
      • Scherens A.
      • Treede R.D.
      • Juckel G.
      Depression and changed pain perception: Hints for a central disinhibition mechanism.
      • Kobayashi N.
      • Hirano K.
      • Nakano M.
      • Ito Y.
      • Ishimori H.
      • Yamawaki M.
      • Tsukahara R.
      • Muramatsu T.
      Prognosis of critical limb ischemia patients with tissue loss after achievement of complete wound healing by endovascular therapy.
      • Munzenmaier D.H.
      • Wilentz J.
      • Cowley Jr., A.W.
      Genetic, epigenetic, and mechanistic studies of temporomandibular disorders and overlapping pain conditions.
      • Neblett R.
      • Hartzell M.M.
      • Cohen H.
      • Mayer T.G.
      • Williams M.
      • Choi Y.
      • Gatchel R.J.
      Ability of the central sensitization inventory to identify central sensitivity syndromes in an outpatient chronic pain sample.
      • Nikolajsen L.
      • Ilkjaer S.
      • Kroner K.
      • Christensen J.H.
      • Jensen T.S.
      The influence of preamputation pain on postamputation stump and phantom pain.
      • Raphael K.G.
      • Janal M.N.
      • Anathan S.
      • Cook D.B.
      • Staud R.
      Temporal summation of heat pain in temporomandibular disorder patients.
      • Sarlani E.
      • Greenspan J.D.
      Why look in the brain for answers to temporomandibular disorder pain?.
      • Staud R.
      Abnormal endogenous pain modulation is a shared characteristic of many chronic pain conditions.
      • Staud R.
      Brain imaging in fibromyalgia syndrome.
      • Vehof J.
      • Zavos H.M.
      • Lachance G.
      • Hammond C.J.
      • Williams F.M.
      Shared genetic factors underlie chronic pain syndromes.
      • Verne G.N.
      • Price D.D.
      Irritable bowel syndrome as a common precipitant of central sensitization.
      • Wasner G.
      Central pain syndromes.
      • Younger J.W.
      • Shen Y.F.
      • Goddard G.
      • Mackey S.C.
      Chronic myofascial temporomandibular pain is associated with neural abnormalities in the trigeminal and limbic systems.
      • Yunus M.B.
      Central sensitivity syndromes: a new paradigm and group nosology for fibromyalgia and overlapping conditions, and the related issue of disease versus illness.
      • Yunus M.B.
      Editorial review: An update on central sensitivity syndromes and the issues of nosology and psychobiology.
      • Yunus M.B.
      Fibromyalgia and overlapping disorders: The unifying concept of central sensitivity syndromes.
      • Yunus M.B.
      The prevalence of fibromyalgia in other chronic pain conditions.
      As we again showed, central sensitivity syndromes are often comorbid with depression, fatigue, anxiety, and sleep disturbance.
      • Aaron L.A.
      • Burke M.M.
      • Buchwald D.
      Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder.
      • Yunus M.B.
      Central sensitivity syndromes: a new paradigm and group nosology for fibromyalgia and overlapping conditions, and the related issue of disease versus illness.
      • Yunus M.B.
      Editorial review: An update on central sensitivity syndromes and the issues of nosology and psychobiology.
      • Yunus M.B.
      Fibromyalgia and overlapping disorders: The unifying concept of central sensitivity syndromes.
      • Yunus M.B.
      Role of central sensitization in symptoms beyond muscle pain, and the evaluation of a patient with widespread pain.
      • Yunus M.B.
      The prevalence of fibromyalgia in other chronic pain conditions.
      DE in our high CPS group might more accurately be characterized as neuropathic ocular pain and be considered an entity distinct from traditional DE. In these patients, whose high rate of manifestation of related CPS suggests a central disorder, perhaps with central sensitization as the underlying mechanism, it appears that their ocular symptoms are but another peripheral manifestation of their central disease. This is further supported by the greater magnitude of ocular and nonocular pain reported by the patients in the high CPS group this study, a finding consistent with those recently reported by Vehof et al, who showed a relationship between DE symptoms and higher forearm pain sensitivity (lower heat pain threshold) using quantitative sensory testing.
      • Vehof J.
      • Kozareva D.
      • Hysi P.G.
      • Harris J.
      • Nessa A.
      • Williams F.K.
      • Bennett D.L.
      • McMahon S.B.
      • Fahy S.J.
      • Direk K.
      • Spector T.D.
      • Hammond C.J.
      Relationship between dry eye symptoms and pain sensitivity.

      Review of Mechanisms of Central Sensitivity That Link Comorbid Pain Conditions

      The idea of a systemic predisposition to pain is plausible through multiple mechanisms, although the specifics of the development of central sensitivity have yet to be determined. The specific postulated mechanisms for the development of central sensitivity associated with DE include aberrations in proinflammatory cytokine signaling and glial cell–neuron interactions. In addition, there is a growing appreciation for the critical role of genetic mechanisms of vulnerability, which underlie these and other potential mechanisms.
      A systemic inflammatory response might cause pain and other manifestations at varying sites via a mechanism that involves circulating proinflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-6 and IL-1b.
      • Laird B.J.
      • McMillan D.C.
      • Fayers P.
      • Fearon K.
      • Kaasa S.
      • Fallon M.T.
      • Klepstad P.
      The systemic inflammatory response and its relationship to pain and other symptoms in advanced cancer.
      Cytokine-mediated mechanisms of pain sensitization might be particularly relevant in the case of neuropathic ocular pain, because recent data suggest that DNA polymorphisms in IL-1 and IL-6 might underlie susceptibility to DE.
      • Na K.S.
      • Mok J.W.
      • Kim J.Y.
      • Joo C.K.
      Proinflammatory gene polymorphisms are potentially associated with Korean non-Sjogren dry eye patients.
      These proinflammatory cytokines can mediate multiple pain syndromes, including neuropathic disorders, via complex mechanisms that include increased spontaneous firing of sensory neurons,
      • Oh S.B.
      • Tran P.B.
      • Gillard S.E.
      • Hurley R.W.
      • Hammond D.L.
      • Miller R.J.
      Chemokines and glycoprotein120 produce pain hypersensitivity by directly exciting primary nociceptive neurons.
      enhanced excitatory neurotransmission, and phenotypic alterations of the primary afferents.
      • Eliav E.
      • Herzberg U.
      • Ruda M.A.
      • Bennett G.J.
      Neuropathic pain from an experimental neuritis of the rat sciatic nerve.
      Various proinflammatory cytokines can also cause fatigue and depression, disorders commonly found to be comorbid with CPS.
      • Scheibel R.S.
      • Valentine A.D.
      • O’Brien S.
      • Meyers C.A.
      Cognitive dysfunction and depression during treatment with interferon-alpha and chemotherapy.
      • Schubert C.
      • Hong S.
      • Natarajan L.
      • Mills P.J.
      • Dimsdale J.E.
      The association between fatigue and inflammatory marker levels in cancer patients: A quantitative review.
      • Trask P.C.
      • Esper P.
      • Riba M.
      • Redman B.
      Psychiatric side effects of interferon therapy: Prevalence, proposed mechanisms, and future directions.
      The presence of increased plasma circulating proinflammatory cytokines in depression has been repeatedly documented, which provided a common link between depression and chronic pain states.
      • McNally L.
      • Bhagwagar Z.
      • Hannestad J.
      Inflammation, glutamate, and glia in depression: A literature review.
      Recently, the complex interactions between glial cells and neurons have received significant attention for their potential role in the pathophysiology of chronic pain.
      • Ji R.R.
      • Berta T.
      • Nedergaard M.
      Glia and pain: Is chronic pain a gliopathy?.
      • Ren K.
      • Dubner R.
      Neuron-glia crosstalk gets serious: Role in pain hypersensitivity.
      Substantial preclinical evidence has revealed that activated microglia and astrocytes mediate the generation and maintenance of several pain states
      • Loggia M.L.
      • Chonde D.B.
      • Akeju O.
      • Arabasz G.
      • Catana C.
      • Edwards R.R.
      • Hill E.
      • Hsu S.
      • Izquierdo-Garcia D.
      • Ji R.R.
      • Riley M.
      • Wasan A.D.
      • Zurcher N.R.
      • Albrecht D.S.
      • Vangel M.G.
      • Rosen B.R.
      • Napadow V.
      • Hooker J.M.
      Evidence for brain glial activation in chronic pain patients.
      in a fashion that is determined by specific genetic polymorphisms and circulating proinflammatory cytokines.
      • Watkins L.R.
      • Hutchinson M.R.
      • Ledeboer A.
      • Wieseler-Frank J.
      • Milligan E.D.
      • Maier S.F.
      Norman Cousins Lecture. Glia as the “bad guys”: Implications for improving clinical pain control and the clinical utility of opioids.
      Glial activation in the brain as a result of stress (eg, traumatic brain injury, systemic inflammatory responses, xenobiotics, etc) can induce the expression of proinflammatory cytokines that directly amplify spinal cord synaptic transmission and induce central sensitization to pain via signal amplification.
      • Ji R.R.
      • Berta T.
      • Nedergaard M.
      Glia and pain: Is chronic pain a gliopathy?.
      Although the causality remains unclear, there is evidence that peripheral and systemic inflammatory responses can lead to microglial activation and depression through interference with monoaminergic, glutamatergic, and neurotrophic systems.
      • McNally L.
      • Bhagwagar Z.
      • Hannestad J.
      Inflammation, glutamate, and glia in depression: A literature review.
      Further research is warranted to determine if these factors represent a shared mechanism of susceptibility to neuropathic ocular pain and other CPS.
      Finally, genetics play a large and increasingly well defined role in conferring the clinical variability observed in nociception, pain processing, and therapeutic response.
      • Costigan M.
      • Belfer I.
      • Griffin R.S.
      • Dai F.
      • Barrett L.B.
      • Coppola G.
      • Wu T.
      • Kiselycznyk C.
      • Poddar M.
      • Lu Y.
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      • Smith S.
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      • Goldman D.
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      • Geschwind D.H.
      • Max M.B.
      • Seltzer Z.
      • Woolf C.J.
      Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1.
      • Costigan M.
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      • Woolf C.J.
      Neuropathic pain: A maladaptive response of the nervous system to damage.
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      • Makarov S.S.
      • Maixner W.
      Genetic basis for individual variations in pain perception and the development of a chronic pain condition.
      • Dib-Hajj S.D.
      • Rush A.M.
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      • Hisama F.M.
      • Novella S.
      • Tyrrell L.
      • Marshall L.
      • Waxman S.G.
      Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons.
      • Faber C.G.
      • Hoeijmakers J.G.
      • Ahn H.S.
      • Cheng X.
      • Han C.
      • Choi J.S.
      • Estacion M.
      • Lauria G.
      • Vanhoutte E.K.
      • Gerrits M.M.
      • Dib-Hajj S.
      • Drenth J.P.
      • Waxman S.G.
      • Merkies I.S.
      Gain of function Nanu1.7 mutations in idiopathic small fiber neuropathy.
      • Kremeyer B.
      • Lopera F.
      • Cox J.J.
      • Momin A.
      • Rugiero F.
      • Marsh S.
      • Woods C.G.
      • Jones N.G.
      • Paterson K.J.
      • Fricker F.R.
      • Villegas A.
      • Acosta N.
      • Pineda-Trujillo N.G.
      • Ramirez J.D.
      • Zea J.
      • Burley M.W.
      • Bedoya G.
      • Bennett D.L.
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      • Ruiz-Linares A.
      A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome.
      The recent results of Vehof et al provide evidence of shared genetic mechanistic factors in multiple comorbid chronic pain conditions, including DE.
      • Vehof J.
      • Zavos H.M.
      • Lachance G.
      • Hammond C.J.
      • Williams F.M.
      Shared genetic factors underlie chronic pain syndromes.
      This group has also reported the heritability of chronic widespread pain, the primary symptom of fibromyalgia, at 58% in women, and suggested the presence of 2 latent traits that underlie chronic widespread pain and various psychoaffective phenotypes, which supports the idea of a common genetic underpinning to functional pain syndromes, depression, and anxiety.
      • Burri A.
      • Ogata S.
      • Vehof J.
      • Williams F.
      Chronic widespread pain: Clinical comorbidities and psychological correlates.
      Genetic polymorphisms can significantly influence plasma levels of proinflammatory mediators, which might explain why certain individuals are prone to hypersensitivity and to a constellation of chronic pain states and depression.
      • Haddy N.
      • Sass C.
      • Maumus S.
      • Marie B.
      • Droesch S.
      • Siest G.
      • Lambert D.
      • Visvikis S.
      Biological variations, genetic polymorphisms and familial resemblance of TNF-alpha and IL-6 concentrations: STANISLAS cohort.
      Collectively, these findings suggest that future genomic studies should be helpful to identify functional variants that are critical to disease susceptibility or resistance. These potential pharmaceutical targets should lead to the discovery of preventive approaches and mechanism-based therapies for DE and possibly other CPS.

      Study Limitations and Conclusions

      As with all studies, our findings need to be considered with our study limitations, which include: a cross-sectional study design, a unique DE population, and the specific metrics used to capture neuropathic ocular pain features. In addition, despite our highly significant findings, the small sample size could make our study underpowered to reveal more subtle findings. Finally, our sample population was biased toward elderly, male veterans and was likely insufficient to assess some CPS like fibromyalgia and temporomandibular disorder, which are more prevalent in women.
      Our findings support the concept that in a subgroup of DE patients, those who described symptoms of neuropathic ocular pain, their eye disease represents a central pain disorder that is heritable and might share causal genetic factors with other CPS. The clinical implications of our findings are great, because they suggest that DE patients with neuropathic ocular pain symptoms might need to be addressed differently than those without neuropathic ocular pain. Specifically, neuropathic pain symptoms are not currently evaluated during DE examinations focused on tear dysfunction and the ocular surface. Therefore, we propose on the basis of our findings, that DE patients also be screened for symptoms of neuropathic ocular pain. Those with neuropathic ocular pain might benefit from further screenings for comorbid pain conditions, depression, and PTSD. DE patients with neuropathic ocular pain with other CPS might also benefit from a multidisciplinary approach to their management, as recommended for other chronic pain states.
      • McGreevy K.
      • Bottros M.M.
      • Raja S.N.
      Preventing chronic pain following acute pain: Risk factors, preventive strategies, and their efficacy.
      When diagnosed, which can be achieved by the use of available questionnaires,
      • Galor A.
      • Zlotcavitch L.
      • Walter S.D.
      • Felix E.R.
      • Feuer W.
      • Martin E.R.
      • Margolis T.P.
      • Sarantopoulos K.D.
      • Levitt R.C.
      Dry eye symptom severity and persistence are associated with symptoms of neuropathic pain.
      neuropathic ocular pain might prove difficult to treat. However, medications useful in treatment of other forms of CPS might eventually prove useful for this subtype of DE patients.

      Acknowledgments

      The authors thank D.A. Lubarsky and K. Candiotti for their generous input and support. The contents of this study do not represent the views of the Department of Veterans Affairs or the United States Government.

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