In a multivariable analysis, considering the effect of demographics, medications, and pain comorbidities on DE, we found that all variables examined associated with ocular pain except for sex, smoking status, tension headache, and neoplasm-related pain. In a similar manner, all variables associated with tear film dysfunction except for tension headache, migraine, and complex regional pain syndrome. The pain diagnoses most closely related to ocular pain were headache (OR 1.96; 95% CI 1.94–1.98), postherpetic neuralgia (OR 1.42; 95% CI 1.35–1.49), and migraine (OR 1.41; 95% CI 1.39–1.44), all P < 0.0005. The pain diagnoses most closely related to tear film dysfunction were postherpetic neuralgia (OR 1.41; 95% CI 1.36–1.45), osteoarthritis (OR 1.39; 95% CI 1.38–1.40), and diabetic neuropathy (OR 1.25; 95% CI 1.24–1.27), all P < 0.0005.
To summarize, we found that within our population, 29.4% of individuals carried a diagnosis of DE, 5.7% of which were subtyped as ocular pain and 26.2% as tear film insufficiency; 2.5% carried both diagnoses. Consistent with other reports,19 the frequency of tear film deficiency steadily increased with age, and both DE types are more common in women. In support of our hypothesis, DE occurred at a higher frequency in those with pain conditions compared with those without pain conditions. In fact, the frequency of DE increased steadily with increased number of pain diagnoses. Our findings are important because they strongly support DE represents a COPC. Moreover, our data showed a stronger relationship between ocular pain and functional pain disorders as compared with tear film dysfunction in both generalized and regionalized syndromes under IASP axis I classification for chronic pain. These data are consistent with underlying somatosensory dysfunction as a shared mechanism among some DE subtypes and other COPC.17,21,48
We previously found that DE symptoms correlated more strongly with nonocular pain and chronic pain conditions than with tear film parameters in a predominantly male veteran population.13 In a complimentary fashion, Vehof et al.49 found that chronic pain syndromes were the most significant predictors of DE symptoms in a predominantly female population in the Netherlands. The current study expands on these findings by demonstrating that correlation between DE and other pain conditions remains strong when considering a large predominantly male population of veterans spanning the entire United States suggesting a mechanistic relationship.
Similar to other COPC, individuals with DE symptoms demonstrate evidence of somatosensory dysfunction.17,48 Specifically, in a large cohort of British women, those with DE symptoms had lower heat pain tolerance in an area remote from the eye (ie, the forearm).48 In a similar manner, in a predominantly male cohort, individuals with DE symptoms were found to have higher temporal summation scores and increased aftersensations to hot and cold pain on the forearm.17 These latter metrics are frequently abnormal in individuals with neuropathic pain and central sensitization.4,26 Furthermore, both conditions have been linked to inflammation and neuroendocrine dysregulation. Systemic inflammation has been implicated in the development and maintenance of central sensitization by means of proinflammatory cytokines like tumor necrosis factor–alpha, interleukin (IL)1 and IL6,22 and activation of glial cells25, with a resultant increase in nociceptor excitability and response. Circulating proinflammatory cytokines have been found elevated in complex regional pain syndrome,35,44 fibromyalgia,28,52 and some forms of chronic back pain.20,53 Ocular surface inflammation is an important component of some forms of DE,39,40 and in animal models, adoptive transfer of CD4+ cells was sufficient to induce disease in naive animals.31 Interestingly, hormonal disturbances have been found to influence maintenance of chronic pain, such as estradiol alterations in individuals TMD and IBS,43 and androgen alterations in DE,47 serving as a possible explanation of the higher frequency in women of DE and other COPC in women.7,27,34,37
As with all studies, our results must be considered bearing in mind the limitations of our research. In this study, data are arranged so that every unique patient seen during the period was placed on a row followed by a yes or no response for the items of interest. Given this format, in this article, we focus on the period prevalence of DE and pain conditions and cannot ascertain incidence or which diagnosis came first. This is an important avenue of future study. In a similar manner, only certain data could be automatically extracted from the database and as such we could not confirm the diagnosis by comparison with clinical notes, determine whether DE was the presenting diagnosis, ascertain the chronicity of DE and other pain diagnoses, or identify which physician made the diagnosis or the intention behind the diagnosis. Furthermore, ICD-9 coding does not capture the full complexity of DE, where manifestations can range from mostly symptoms, mostly signs, or by an overlap in symptoms and signs. Because of inherent limitation with ICD-9 coding methodology, we were unable to access information necessary to use IASP axis II, III, IV, and V classifications; as a result, this study primarily used IASP axis I regional classification of chronic pain. Finally, veterans represent a unique population with a male predominance and a high frequency of mental health disorders and chronic pain diagnoses. Despite these limitations, our study provides the benefit of using a very large nationwide database to evaluate our research questions. To conclude, this study provides further evidence that the frequency of DE increases with increasing numbers of nonocular pain conditions and should be considered a COPC group member. These findings suggest that pain specialists who screen for DE symptoms in those with COPC, and work with eye care providers to optimize both topical and systemic therapy, may improve patient outcomes.
The authors have no conflict of interest to declare.
Supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Clinical Sciences Research EPID-006-15S (A. Galor), NIH Center Core Grant P30EY014801, R01EY026174 (A. Galor), Research to Prevent Blindness Unrestricted Grant, and NIDCR 1R01DE022903 (R. C. Levitt).
. The definition and classification of dry eye
disease: report of the definition and classification subcommittee of the International Dry Eye
WorkShop (2007). Ocul Surf 2007;5:75–92.
. The epidemiology of dry eye
disease: report of the epidemiology subcommittee of the International Dry Eye
WorkShop (2007). Ocul Surf 2007;5:93–107.
. Relieving pain in America: A blueprint for transforming prevention, care, education, and research. Washington (DC): National Academies Press, 2011.
. Backonja MM, Walk D, Edwards RR, Sehgal N, Moeller-Bertram T, Wasan A, Irving G, Argoff C, Wallace M. Quantitative sensory testing in measurement of neuropathic pain phenomena and other sensory abnormalities. Clin J Pain 2009;25:641–7.
. Benatti C, Blom JM, Rigillo G, Alboni S, Zizzi F, Torta R, Brunello N, Tascedda F. Disease-induced neuroinflammation and depression. CNS Neurol Disord Drug Targets 2016;15:414–33.
. Burbelo PD, Ambatipudi K, Alevizos I. Genome-wide association studies in Sjogren's syndrome: what do the genes tell us about disease pathogenesis? Autoimmun Rev 2014;13:756–61.
. Crane AM, Levitt RC, Felix ER, Sarantopoulos KD, McClellan AL, Galor A. Patients with more severe symptoms of neuropathic ocular pain report more frequent and severe chronic overlapping pain conditions
and psychiatric disease. Br J Ophthalmol 2016;101:227–31.
. Diatchenko L, Nackley AG, Slade GD, Fillingim RB, Maixner W. Idiopathic pain disorders–pathways of vulnerability. Pain 2006;123:226–30.
. Diatchenko L, Slade GD, Nackley AG, Bhalang K, Sigurdsson A, Belfer I, Goldman D, Xu K, Shabalina SA, Shagin D, Max MB, Makarov SS, Maixner W. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet 2005;14:135–43.
. Finan PH, Smith MT. The comorbidity of insomnia, chronic pain, and depression: dopamine as a putative mechanism. Sleep Med Rev 2013;17:173–83.
. Galor A, Batawi H, Felix ER, Margolis TP, Sarantopoulos KD, Martin ER, Levitt RC. Incomplete response to artificial tears is associated with features of neuropathic ocular pain. Br J Ophthalmol 2016;100:745–9.
. Galor A, Covington D, Levitt AE, McManus KT, Seiden B, Felix ER, Kalangara J, Feuer W, Patin DJ, Martin ER, Sarantopoulos KD, Levitt RC. Neuropathic ocular pain due to dry eye
is associated with multiple comorbid chronic pain syndromes. J Pain 2016;17:310–18.
. Galor A, Felix ER, Feuer W, Shalabi N, Martin ER, Margolis TP, Sarantopoulos CD, Levitt RC. Dry eye
symptoms align more closely to non-ocular conditions than to tear film parameters. Br J Ophthalmol 2015;99:1126–9.
. Galor A, Feuer W, Lee DJ, Florez H, Faler AL, Zann KL, Perez VL. Depression, post-traumatic stress disorder, and dry eye
syndrome: a study utilizing the national United States Veterans Affairs administrative database. Am J Ophthalmol 2012;154:340–6. e342.
. Galor A, Feuer W, Lee DJ, Florez H, Venincasa VD, Perez VL. Ocular surface parameters in older male veterans. Invest Ophthalmol Vis Sci 2013;54:1426–33.
. Galor A, Levitt RC, Felix ER, Martin ER, Sarantopoulos CD. Neuropathic ocular pain: an important yet underevaluated feature of dry eye
. Eye (Lond) 2015;29:301–12.
. Galor A, Levitt RC, McManus KT, Kalangara JP, Seiden BE, Park JJ, Covington DB, Sarantopoulos CD, Felix ER. Assessment of somatosensory function in patients with idiopathic dry eye
symptoms. JAMA Ophthalmol 2016;134:1290–8.
. Galor A, Seiden BE, Park JJ, Feuer WJ, McClellan AL, Felix ER, Levitt RC, Sarantopoulos CD, Wallace DM. The association of dry eye
symptom severity and comorbid insomnia in US veterans. Eye Contact Lens 2017.
. Gayton JL. Etiology, prevalence, and treatment of dry eye
disease. Clin Ophthalmol 2009;3:405–12.
. Heffner KL, France CR, Trost Z, Ng HM, Pigeon WR. Chronic low back pain, sleep disturbance, and interleukin-6. Clin J Pain 2011;27:35–41.
. Kalangara JP, Galor A, Levitt RC, Covington DB, McManus KT, Sarantopoulos CD, Felix ER. Characteristics of ocular pain complaints in patients with idiopathic dry eye
symptoms. Eye Contact Lens 2016;23:192–8.
. Laird BJ, McMillan DC, Fayers P, Fearon K, Kaasa S, Fallon MT, Klepstad P. The systemic inflammatory response and its relationship to pain and other symptoms in advanced cancer. Oncologist 2013;18:1050–5.
. Lessard CJ, Li H, Adrianto I, Ice JA, Rasmussen A, Grundahl KM, Kelly JA, Dozmorov MG, Miceli-Richard C, Bowman S, Lester S, Eriksson P, Eloranta ML, Brun JG, Goransson LG, Harboe E, Guthridge JM, Kaufman KM, Kvarnstrom M, Jazebi H, Cunninghame Graham DS, Grandits ME, Nazmul-Hossain AN, Patel K, Adler AJ, Maier-Moore JS, Farris AD, Brennan MT, Lessard JA, Chodosh J, Gopalakrishnan R, Hefner KS, Houston GD, Huang AJ, Hughes PJ, Lewis DM, Radfar L, Rohrer MD, Stone DU, Wren JD, Vyse TJ, Gaffney PM, James JA, Omdal R, Wahren-Herlenius M, Illei GG, Witte T, Jonsson R, Rischmueller M, Ronnblom L, Nordmark G, Ng WF, Registry UKPSsS, Mariette X, Anaya JM, Rhodus NL, Segal BM, Scofield RH, Montgomery CG, Harley JB, Sivils KL. Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjogren's syndrome. Nat Genet 2013;45:1284–92.
. Li Y, Zhang K, Chen H, Sun F, Xu J, Wu Z, Li P, Zhang L, Du Y, Luan H, Li X, Wu L, Li H, Wu H, Li X, Li X, Zhang X, Gong L, Dai L, Sun L, Zuo X, Xu J, Gong H, Li Z, Tong S, Wu M, Li X, Xiao W, Wang G, Zhu P, Shen M, Liu S, Zhao D, Liu W, Wang Y, Huang C, Jiang Q, Liu G, Liu B, Hu S, Zhang W, Zhang Z, You X, Li M, Hao W, Zhao C, Leng X, Bi L, Wang Y, Zhang F, Shi Q, Qi W, Zhang X, Jia Y, Su J, Li Q, Hou Y, Wu Q, Xu D, Zheng W, Zhang M, Wang Q, Fei Y, Zhang X, Li J, Jiang Y, Tian X, Zhao L, Wang L, Zhou B, Li Y, Zhao Y, Zeng X, Ott J, Wang J, Zhang F. A genome-wide association study in Han Chinese identifies a susceptibility locus for primary Sjogren's syndrome at 7q11.23. Nat Genet 2013;45:1361–5.
. Loggia ML, Chonde DB, Akeju O, Arabasz G, Catana C, Edwards RR, Hill E, Hsu S, Izquierdo-Garcia D, Ji RR, Riley M, Wasan AD, Zurcher NR, Albrecht DS, Vangel MG, Rosen BR, Napadow V, Hooker JM. Evidence for brain glial activation in chronic pain patients. Brain 2015;138:604–15.
. Maier C, Baron R, Tolle TR, Binder A, Birbaumer N, Birklein F, Gierthmuhlen J, Flor H, Geber C, Huge V, Krumova EK, Landwehrmeyer GB, Magerl W, Maihofner C, Richter H, Rolke R, Scherens A, Schwarz A, Sommer C, Tronnier V, Uceyler N, Valet M, Wasner G, Treede RD. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes. PAIN 2010;150:439–50.
. Maixner W, Fillingim RB, Williams DA, Smith SB, Slade GD. Overlapping chronic pain conditions: implications for diagnosis and classification. J Pain 2016;17(9 suppl):T93–107.
. Mendieta D, De la Cruz-Aguilera DL, Barrera-Villalpando MI, Becerril-Villanueva E, Arreola R, Hernandez-Ferreira E, Perez-Tapia SM, Perez-Sanchez G, Garces-Alvarez ME, Aguirre-Cruz L, Velasco-Velazquez MA, Pavon L. IL-8 and IL-6 primarily mediate the inflammatory response in fibromyalgia patients. J Neuroimmunol 2016;290:22–5.
. Miljanovic B, Dana R, Sullivan DA, Schaumberg DA. Impact of dry eye
syndrome on vision-related quality of life. Am J Ophthalmol 2007;143:409–15.
. Na KS, Mok JW, Kim JY, Joo CK. Proinflammatory gene polymorphisms are potentially associated with Korean non-Sjogren dry eye
patients. Mol Vis 2011;17:2818–23.
. Niederkorn JY, Stern ME, Pflugfelder SC, De Paiva CS, Corrales RM, Gao J, Siemasko K. Desiccating stress induces T cell-mediated Sjogren's Syndrome-like lacrimal keratoconjunctivitis. J Immunol 2006;176:3950–7.
. Ong ES, Alghamdi YA, Levitt RC, McClellan AL, Lewis G, Sarantopoulos CD, Felix ER, Galor A. Longitudinal examination of frequency of and risk factors for severe dry eye
symptoms in US veterans. JAMA Ophthalmol 2016;135:116–23.
. Pouyeh B, Viteri E, Feuer W, Lee DJ, Florez H, Fabian JA, Perez VL, Galor A. Impact of ocular surface symptoms on quality of life in a United States veterans affairs population. Am J Ophthalmol 2012;153:1061–6 e1063.
. Reed BD, Harlow SD, Sen A, Edwards RM, Chen D, Haefner HK. Relationship between vulvodynia and chronic comorbid pain conditions. Obstet Gynecol 2012;120:145–51.
. Ritz BW, Alexander GM, Nogusa S, Perreault MJ, Peterlin BL, Grothusen JR, Schwartzman RJ. Elevated blood levels of inflammatory monocytes (CD14+ CD16+) in patients with complex regional pain syndrome. Clin Exp Immunol 2011;164:108–17.
. Rosenthal P, Borsook D. Ocular neuropathic pain. Br J Ophthalmol 2016;100:128–34.
. Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye
syndrome among US women. Am J Ophthalmol 2003;136:318–26.
. Schein OD, Tielsch JM, Munoz B, Bandeen-Roche K, West S. Relation between signs and symptoms of dry eye
in the elderly. A population-based perspective. Ophthalmology 1997;104:1395–401.
. Stern ME, Pflugfelder SC. Inflammation in dry eye
. Ocul Surf 2004;2:124–30.
. Stern ME, Schaumburg CS, Pflugfelder SC. Dry eye
as a mucosal autoimmune disease. Int Rev Immunol 2013;32:19–41.
. Stonecipher K, Perry HD, Gross RH, Kerney DL. The impact of topical cyclosporine A emulsion 0.05% on the outcomes of patients with keratoconjunctivitis sicca. Curr Med Res Opin 2005;21:1057–63.
. Thieme K, Turk DC, Flor H. Comorbid depression and anxiety in fibromyalgia syndrome: relationship to somatic and psychosocial variables. Psychosom Med 2004;66:837–44.
. Traub RJ, Cao DY, Karpowicz J, Pandya S, Ji Y, Dorsey SG, Dessem D. A clinically relevant animal model of temporomandibular disorder and irritable bowel syndrome comorbidity. J Pain 2014;15:956–66.
. Uceyler N, Eberle T, Rolke R, Birklein F, Sommer C. Differential expression patterns of cytokines in complex regional pain syndrome. PAIN 2007;132:195–205.
. Vassend O, Krogstad BS, Dahl BL. Negative affectivity, somatic complaints, and symptoms of temporomandibular disorders. J Psychosom Res 1995;39:889–99.
. Veasley C, Clare D, Clauw DJ, Cowley T, Nguyen RHN, Reinecke P, Vernon SD, Williams DA. Impact of chronic overlapping pain conditions
on public health and the urgent need for safe and effective treatment: 2015 analysis and policy recommendations. Chronic Pain Res Alliance 2015;2016:5.
. Vehof J, Hysi PG, Hammond CJ. A metabolome-wide study of dry eye
disease reveals serum androgens as biomarkers. Ophthalmology 2017;124:505–11.
. Vehof J, Kozareva D, Hysi PG, Harris J, Nessa A, Williams FK, Bennett DL, McMahon SB, Fahy SJ, Direk K, Spector TD, Hammond CJ. Relationship between dry eye
symptoms and pain sensitivity. JAMA Ophthalmol 2013;131:1304–8.
. Vehof J, Sillevis Smitt-Kamminga N, Nibourg SA, Hammond CJ. Predictors of discordance between symptoms and signs in dry eye
disease. Ophthalmology 2017;124:280–6.
. Vehof J, Wang B, Kozareva D, Hysi PG, Snieder H, Hammond CJ. The heritability of dry eye
disease in a female twin cohort. Invest Ophthalmol Vis Sci 2014;55:7278–83.
. Vehof J, Zavos HM, Lachance G, Hammond CJ, Williams FM. Shared genetic factors underlie chronic pain syndromes. PAIN 2014;155:1562–8.
. Wallace DJ, Gavin IM, Karpenko O, Barkhordar F, Gillis BS. Cytokine and chemokine profiles in fibromyalgia, rheumatoid arthritis and systemic lupus erythematosus: a potentially useful tool in differential diagnosis. Rheumatol Int 2015;35:991–6.
. Wang H, Ahrens C, Rief W, Gantz S, Schiltenwolf M, Richter W. Influence of depression symptoms on serum tumor necrosis factor-alpha of patients with chronic low back pain. Arthritis Res Ther 2010;12:R186.
. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. PAIN 2011;152:S2–15.
. Yunus MB. Central sensitivity syndromes: a new paradigm and group nosology for fibromyalgia and overlapping conditions, and the related issue of disease versus illness. Semin Arthritis Rheum 2008;37:339–52.
. Yunus MB. Editorial review: an update on central sensitivity syndromes and the issues of nosology and psychobiology. Curr Rheumatol Rev 2015;11:70–85.