Introduction

Chronic pain is a pain that persists or recurs for longer than 3 months. With an estimated 20% prevalence in the general population worldwide it is highly common. It comes with significant direct and indirect costs for society. In the United States, these costs are higher than the combined costs of cancer, diabetes, and heart disease, and are estimated to be over $500 billion per year. In the new ICD-11 classification chronic pain is systematically classified as either primary pain, including disorders such as chronic widespread pain (CWP), chronic musculoskeletal pain, primary headache disorders, chronic pelvic pain, and irritable bowel syndrome (IBS), or as secondary pain including disorders such as cancer-related pain, postsurgical pain, neuropathic pain, secondary headache or orofacial pain, visceral pain, and secondary musculoskeletal pain. There is increasing recognition that many chronic pain conditions often coexist, leading to the concept of chronic overlapping pain conditions (COPCs).

Indeed, numerous systemic pain conditions have been associated with dry eye disease and dry eye (like) symptoms, suggesting dry eye might be a COPC as well. Fig. 9.1 illustrates this overlap. There are many similarities and shared pathophysiological mechanisms between dry eye and these disorders that may underlie this association. Increased awareness and recognition of associated systemic pain conditions and their pathophysiological mechanisms might help an ophthalmic practitioner fully understand the clinical picture of dry eye and optimize patient’s treatment. Similarly, physicians looking after patients with systemic pain should be aware of dry eye disease being a prevalent comorbidity with serious impact.

An example of how dry eye overlaps with other chronic pain conditions.

Created by Emily Moschowits.

Shared Epidemiological Factors

Both dry eye and systemic pain conditions are much more prevalent in women. Other important risk factors are also largely similar, such as older age, mental health problems, sleep disturbance, reduced physical activity, a history of smoking, heritable factors, nutrition, surgical interventions, and a history of trauma. A classical twin study in the United Kingdom investigated genetic and environment interrelations between fibromyalgia (FM), IBS, chronic pelvic pain, and DED. It revealed that these four disorders share a latent underlying factor that is highly heritable (66%), which accounts for clustering of these conditions in patients. This underlying latent factor of chronic pain predisposition accounted for 15% of the variance of DED in the investigated population. This indicates that both shared genetic and shared environmental factors with other systemic pain conditions underlie dry eye, explaining the overlap of disorders in patients.

Shared Clinical Characteristics

Both dry eye and systemic pain conditions are chronic diseases, and both show a lack of response to treatment. Symptoms of both often include dysesthesias (meaning “abnormal sensations”) such as a burning or throbbing feeling, or the feeling of pins and needles. One of the hallmarks of both is discordance between subjective symptoms and objective signs. Moreover, a study of 648 dry eye patients (83% women) in the Netherlands found systemic pain conditions to be the strongest predictor of discordance between symptoms and signs of dry eye. IBS, FM, and chronic pelvic pain were all highly associated with greater symptoms compared to signs. In addition, depression and osteoarthritis were also associated with more symptoms than signs. A similar study in the United States, in men only, found similar results with greater symptoms than signs in persons with arthritis, chronic pain outside the eye, posttraumatic stress disorder (PTSD), anxiety, and depression.

Neuropathic Pain

Neuropathic pain is pain caused by a lesion or disease of the somatosensory nervous system, and often plays a role in chronic pain. Somatosensory dysfunction may be the origin of dry eye symptoms, particularly in patients with limited or no abnormalities of the ocular surface with a standard eye exam. This dysfunction may be either at the periphery (e.g., corneal nerves) or central, within the central nervous system. At the periphery, corneal nerve abnormalities can lead to a spectrum of disease, ranging from hyposensitivity and neurotrophy with epitheliopathy to hypersensitivity with pain. Inflammation at the ocular surface in dry eye can lower the threshold of neuron activation, and both intensity and duration of pulses can increase with time. When acute pain becomes chronic, it can undergo centralization: despite limited input from the peripheral nervous system, the central nervous system responds as if there are high levels of painful stimuli and patients become hypersensitive to pain. This process is often referred to as the wind-up or temporal summation. Patients can experience neuropathic pain from stimuli that are normally not painful (allodynia) or have an increased sensitivity to painful stimuli (hyperalgesia), but pain may also arise spontaneously.

Increased Pain Sensitivity and Nerve Abnormalities

Altered findings on quantitative sensory testing (QST) testing, such as lower pain tolerance and higher pain sensitivity, are very common with neuropathic pain and in systemic pain conditions. Also dry eye has been associated with altered QST. In a UK cohort QST using a heat stimulus on the forearm was used to assess pain sensitivity and pain tolerance in 1635 females. Both pain sensitivity was higher and pain tolerance was lower in those with DED than in those without DED. Participants with a below median pain sensitivity were found to have almost twice as often dry eye pain symptoms such as light sensitivity, gritty feeling, and painful eyes than persons with an above median pain sensitivity. Similar results were found in a predominantly male cohort in the United States, with severity of neuropathic-like dry eye pain (symptoms such as burning and evoked pain to wind and light) particularly correlating with QST. Moreover, increased pain sensitivity, as measured by QST metrics, was also associated with more symptoms compared to signs. In addition, dry eye and neuropathic pain share similarities in altered nerve anatomy such as nerve density and length.

Comorbid Mental Health Disorders

Systemic pain conditions, neuropathic pain, and dry eye are also highly comorbid with mental health disorders and influenced by psychological factors that can impact symptoms and an individual’s experience of pain. ^{, ,} In a US cohort it was found that dry eye symptoms align more with nonocular pain and PTSD scores than with dry eye signs, explaining 35%–40% of the variability of symptoms. A Korean study found that depression scores correlated with dry eye symptoms scores, but not with dry eye signs. Another study in patients with symptoms of dry eye found that in those with high neuropathic ocular pain symptoms pain intensity ratings were higher, and mental health scores more abnormal compared to those with low or no neuropathic ocular symptoms.

Inflammatory Factors

Finally, both neuropathic pain and dry eye may share similarities in inflammatory mechanisms. Among the studies that investigated inflammatory mediators in various systemic pain conditions, levels of PGE ₂ , IL-1, IL-6, TNF, are among the most consistently increased. These mediators have also been found to be increased in tears of DED patients, and may play a role in sensitization of peripheral corneal nociceptors.

The findings above suggest that increased pain sensitivity, neuropathic pain, and other pain modifying mechanisms are responsible for a share of the symptom burden of dry eye, particularly in patients with comorbid systemic pain and mental health disorders. Fig. 9.2 schematically summarizes mechanisms underlying the link between systemic pain conditions and DED. Although pain management may fall outside the scope of practice of many eye practitioners, it is important to recognize neuropathic pain, particularly when symptoms are worse than clinical signs. When recognized, patients can be educated about the origin of their symptoms and their treatment can be optimized by a multidisciplinary approach including pain specialists. The TFOS DEWS II Definition and Classification Report added neuropathic pain and referral for pain management in its main clinical decision algorithm and classification scheme of DED. Box 9.1 presents an overview of systemic pain conditions that have been associated with an increased prevalence of DED and/or dry eye symptoms in clinical and population-based studies. The systemic pain disorders most studied in this context will be discussed in the next section.

Dry eye and chronic pain share many external and internal risk factors that contribute to the complex nature of both.

Created by Emily Moschowits.

Fibromyalgia

FM is a chronic disorder and probably a subgroup of CWP, which is characterized by widespread musculoskeletal pain in all four quadrants of the body, and in the neck and back. FM is CWP of more than a 3-month duration, with mechanical hyperalgesia at least 11 tender-point sites. It is accompanied by symptoms such as fatigue and sleep and mood problems. Its etiology is largely unknown, but genetic factors, stressful life events, and peripheral and central mechanisms play a role. The prevalence in the general population is around 2%–5%, with women six times more affected than men. Over half of patients will have a diagnosis of depression in their life, and other chronic pain conditions such as head and jaw pain and IBS are also highly prevalent. ^, The revised 2010 diagnostic criteria of FM by the American College of Rheumatology included numerous somatic symptoms as additional minor criteria, including blurred vision and dry eye.

Of all systemic pain disorders, FM is probably the most studied in relation to DED. Several studies have shown dry eye prevalence to be much higher in FM patients than in controls and vice versa. FM disease activity was found to correlate with dry eye severity. In addition, half a dozen studies on corneal nerve structures in FM patients have uniformly reported abnormalities in nerve structures, such as a lower nerve density and nerve count compared to controls. Findings on corneal sensitivity, however, were less consistent among studies. A recent study showed that one-third of FM patients with dry mouth and/or dry eye tested positive for Sjögren’s syndrome autoantibodies. The majority of these only tested positive for the novel tissue-specific autoantibodies, that are observed in early stage Sjögren’s syndrome, such as SP-1, CA6, and PSP, and not for the classic autoantibodies such as SS-A/Ro and SS-B/La. This indicates that autoimmunity and early-stage Sjögren’s syndrome may be involved in at least some FM patients.

Irritable Bowel Syndrome

IBS is a functional gastrointestinal disorder with recurrent symptoms of abdominal pain and a change in form or frequency of stool. It is a common disorder, with an estimated prevalence of 5%–10% in the general population. Its pathophysiology is not well understood, but it is widely accepted that there is dysfunctional communication between the brain and the gut that leads to visceral hypersensitivity, altered CNS processing and motility disturbances. Pain sensitivity, bacterial overgrowth of the small intestine, neurotransmitters, genetic factors, and food sensitivity have also been proposed to play a role. Diagnosis is based on symptoms and exclusion of signs of other disorders. The most important risk factors of IBS include acute enteric infection, female sex, and psychological comorbidities.

IBS has been associated with dry eye in clinical and population studies. ^{, , ,} Not only dry eye symptoms but also signs such as Schirmer test and TBUT have been found to be significantly worse in IBS patients compared to controls, which may also suggest a common inflammatory pathogenesis. Like in dry eye, proinflammatory cytokines, such as IL-1, IL-6, and TNF-α, and T-cell activation have been shown to be increased in IBS patients. Also, the transient receptor potential cation channel subfamily M member 8 (TRPM8) has been described in the pathophysiology of both IBS and dry eye. This channel is the primary thermoreceptor for responses to cold stimuli and can be found in multiple organs, including the gut where it plays a role in colonic spontaneous motility and the cornea where it plays a role in regulating basal tear flow. Dysfunction may lead to inflammatory or neuropathic pain and cold allodynia and hyperalgesia.

Chronic Pelvic Pain and Bladder Pain

Chronic pelvic pain is a disabling, persistent pain within the pelvis in women, lasting more than 6 months. Its prevalence lies between 4% and 16% in women. Centralized pain is widely considered as the main pathophysiology. It may or may not be associated with initial local pelvic pathology. It can, for example, originate from endometriosis, where acute pain associated with this condition becomes centralized after several months. IBS and bladder pain syndrome are also highly comorbid in women who suffer chronic pelvic pain. It has a strong association with previous physical and emotional trauma. Although the link between DED and CPP has not been studied as much as other pain conditions, it was among the strongest risk factors of dry eye in population-based studies that included it in the set of investigated risk factors. It was also one of the three pain disorders that were found to have shared genetic factors with DED (in addition to FM and IBS).

An overactive bladder and bladder pain syndrome (interstitial cystitis) have been associated with systemic autoimmune disease, particularly Sjögren’s syndrome, in several clinical samples. Recurring cystitis was found as an independent risk factor of dry eye symptoms in a large population-based study. Autoantibodies to the muscarinic M3 receptor, which plays a role in tear secretion and bladder contraction, may underlie these associations.

Migraine and Other Headache Disorders

Migraine is considered a neurovascular condition that clinically manifests as recurrent headache attacks with a duration of 4–72 h. Typical features are a mostly unilateral, pulsating head pain, aggravation by physical activity, and accompanying symptoms such as nausea, vomiting, photo- and phonophobia, and visual and hemisensory disturbances. It has an estimated 1-year prevalence of around 15% in the general population, with females being more affected than males (3:1). Its pathogenesis is poorly understood, but the trigeminal nerve and its axonal projections to the trigeminovascular system are involved. As such, in both migraine and dry eye pathways of the trigeminal system are involved, with photophobia being a shared common symptom. Numerous studies have found an increased risk of a dry eye diagnosis or dry eye symptoms in migraine patients. ^{, ,} Altered tear function or other objective signs of dry eye in migraine patients are however less apparent. ^,

Corneal nerves have been studied in the context of migraine, but results are not uniform and may vary between populations. Corneal nerve lengths were found to be lower in individuals with migraine and concomitant photophobia than in controls or in individuals with migraine without photophobia. One study found lower nerve density in migraine patients compared to controls, while another study found higher corneal nerve density. Only one study investigated corneal sensitivity and found borderline significant higher sensitivity in migraine patients compared to controls. No shared genetic factors were found between migraine and other chronic pain syndromes including DED in a twin study, suggesting that other factors may play a role in the association between the two. For example, some authors suggest inflammatory processes could underlie the association between the two, such as T-lymphocyte–mediated inflammation and increased levels of inflammatory mediators such as calcitonin gene-related peptide and interleukines. ^, In migraine, inflammatory mediators may lead to hypersensitivity of trigeminal ganglion neurons via increased plasma extravasation. Also, increased sensitivity to pain, cold, and heat was found in individuals with migraine. ^, Migraine has also been associated with Sjögren’s syndrome and other connective tissue diseases.

Other primary headache disorders may also give eye pain, tearing, or periocular pain that may mimic dry eye symptoms, such as tension-type headaches and the trigeminal autonomic cephalalgias (cluster headache, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing).

Osteoarthritis

Osteoarthritis is a complex progressive degenerative disease of multiple joint tissues. It can affect any joint and can lead to severe pain, stiffness, and disability. Older age and female sex are important risk factors. Similar to dry eye, it has a vicious circle of pathophysiology, that includes tissue inflammation, changes in synovial fluid, articular cartilage degeneration, and osteochondral alterations, leading to bone changes and damage. A handful of studies have investigated the link between osteoarthritis and dry eye, and found a clearly increased risk of DED in patients with osteoarthritis. ^{, , ,} Osteoarthritis may be comorbid with or misdiagnosed for arthritis in connective tissue disease, which may explain part of the associated risk found in studies. It was, however, also found to be a highly significant independent risk factor of dry eye, after correction for numerous autoimmune and connective tissue disorders in a large population-based study. Similar to DED, osteoarthritis is associated with increased pain sensitivity on QST. ^, Another link between the two may be impaired function of the viscoelastic properties of both the tears and the synovial fluid, via, e.g., hyaluronic acid or lubricin. Hyaluronic acid plays an important role as a lubricant in the human body has the highest concentrations found in the joints and eyes, and promotes corneal epithelial wound healing. One study found a diagnosis of tear film dysfunction twice as often in persons with osteoarthritis compared to controls, indicating that their link is not limited to just increased pain sensitivity.

Temporomandibular Joint Disorders

Temporomandibular joint disorders (TMDs) are characterized by pain or dysfunction of the temporomandibular joint and the muscles of mastication. Their prevalence is around 5%–12% in the general population. The disorders have associated symptoms such as headache, earache, restricted mandibular movement, and noises during jaw movement. The typical headache associated with TMD is pain that radiates to the jaw, temple, or forehead. Chronic TMD is considered a biopsychosocial pain condition with many features similar to other chronic pain disorders, including lower pain tolerance than controls, a poor correlation between pain severity and tissue pathology, and a link with anxiety, depression, posttraumatic stress, and a history of abuse. FM and IBS are also highly comorbid. In a large retrospective study investigating ICD-codes in the United States, TMD was associated with a 2.4 times higher risk of dry eye. TMD is also more common in patients with Sjögren’s syndrome, which may explain part of the associated risk of dry eye. ^,

Small Fiber Neuropathy

Small fiber neuropathy (SFN) is a subtype of neuropathy characterized by selective involvement of thinly myelinated and unmyelinated sensory fibers. The neuropathy manifests clinically with isolated sensory disturbances, isolated autonomic disorders, or both. Persons can have severe pain attacks that typically start in the hands or feet, but can increase to a more generalized body pain. Its pathophysiology is complex, with immune-mediated, metabolic, toxic, and genetic factors likely playing a role. It has been associated with many autoimmune disorders, including Sjögren’s syndrome, and also with hyperalgesia, allodynia, and several chronic pain syndromes. The condition is further associated with urinary and bowel disorders, palpitations, orthostatic hypertension, and also dry eye and mouth. An in vivo corneal confocal microscopy study found signs of trigeminal nerve injury in patients with SFN, with reduced corneal nerve fiber density and decreased total number of corneal nerves.

Central Pain Syndrome

Central pain syndrome is a neurological condition consisting of constant pain due to sensitization of the pain system after damage to the CNS, e.g., by an accident, surgery, stroke, or autoimmune disease. A diagnosis of central pain syndrome was associated with a two times higher risk of dry eye.

Complex Regional Pain Syndrome

The complex regional pain syndrome (CRPS) is a neuropathic pain syndrome after injury, characterized by disabling pain, swelling, and impaired motor function. It is most prevalent in extremities but can also present in the orofacial region. Pain and hyperalgesia can spread to uninjured sites of the ipsilateral side of the body, and even to the whole body. Visual discomfort and photophobia are common in patients with CRPS. A study investigating visual discomfort thresholds to a light source that increased in intensity found lower thresholds in patients than in controls. Thresholds were also found to be lower on the CRPS-affected than unaffected side. Indeed, a diagnosis of CRPS was highly associated with a dry eye diagnosis in a US veteran population. Visual discomfort in CRPS may be explained by abnormal processing of nociceptive input in the ipsilateral trigeminal–medullary region of the brainstem.

Other Systemic Pain Conditions

There are several other pain conditions that have been associated with dry eye that point to a much more widespread association between chronic pain conditions and DED. A large population-based study in the Netherlands with over 78,000 participants found repetitive strain injury, disc herniation, carpal tunnel syndrome, and chronic back pain all to be independently associated with dry eye, even after correction for confounding disorders such as depression, FM, IBS, and osteoarthritis. Multiple chemical sensitivity (sometimes called sick building syndrome) is another disorder highly associated with sensitization, that can also lead to burning or sore eyes. It is characterized by nonspecific symptoms in multiple organ systems due to exposure to low-level chemicals.

Mental Health Disorders and Psychological Factors that can Influence Pain

The perception of pain can be highly influenced by psychological factors and mental health disorders such as depression, anxiety, and stress. Underlying mechanisms include disinhibition of the central pain regulatory system and inhibition of the central pleasure system and of the psychomotor facilitatory system. ^, Comorbidity between chronic pain and depression was found to be higher in women. Interestingly, in depressed people there is a particular increased pain sensitivity for exteroceptive stimuli, which are also important in the etiology of dry eye. Depression and anxiety are also highly prevalent in dry eye. ^, A systematic review found an average prevalence of depression of 29% in dry eye patients, which was the highest rate among several common eye disorders investigated. The association between depression and dry eye is likely to be bidirectional, with dry eye symptoms leading to depressive symptoms as well.

PTSD has also been associated with a highly increased risk of dry eye symptoms. PTSD not only shares similarities with depression but also leads to amplified emotional reactions including responses to painful stimuli. Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis, is a complex disease with a constellation of symptoms such as a disabling fatigue, postexertional malaise, muscle and joint pain, headaches, and cognitive impairment. Several studies showed an increased prevalence of dry eye in persons with CFS. ^{, ,}

Poor sleep quality can also increase pain sensitivity. ^, Insomnia is a common comorbid disorder of both dry eye and neuropathic pain. ^, Every component of sleep quality was found to be highly affected in dry eye patients, particularly in those with frequent symptoms, even after correction for comorbid pain and psychiatric disorders. As for depression, the relationship between sleep quality and dry eye is also likely to be bidirectional.

Referred Pain and Other Ocular and Orbital Disorders Mimicking Dry Eye Symptoms

An often-overlooked etiology of dry eye symptoms is the group of disorders that give referred pain or produce symptoms that mimic dry eye. Headache disorders are an important group, and have been discussed in section Migraine and Other Headache Disorders above. Trigeminal neuralgia is characterized by spontaneous and severe shock-like face pain lasting for seconds to minutes. It can also present with a less severe constant burning or throbbing pain between attacks. The maxillary nerve (v2) is most often affected, but all branches including the ophthalmic nerve (v1) may be affected. Sinusitis was found to be an independent risk factor of dry eye in a large population-based study. It may give a throbbing pain or pressure around the eyes that might be confused with dry eye. Similarly, odontogenic pain and oral surgery may affect trigeminal function and give referred ocular pain. Ocular motor cranial nerve palsies due to ischemia may produce a frontal headache pain, brow pain, and ocular pain.

Other ocular and orbital disorders that may produce similar (pain) symptoms as dry eye and that are often overlooked by standard ocular exams are trochleodynia, intermittent angle closure, posterior scleritis, Tolosa Hunt syndrome, and cavernous carotid fistula. Benign essential blepharospasm may not only be caused by dry eye but can also produce dry eye like symptoms. ^, It is also important to rule out any refractive error problem (e.g., latent hypermetropia) in patients who have both headache and dry eye like symptoms. Digital eye strain (also called trigeminal dysphoria) is another cause that can give both symptoms of headache and dry eye.