Nociplastic pain among individuals with chronic ocular surface pain: One cause for "pain without stain"?

In 2016, the International Association of the Study of Pain (IASP) assembled an international community of pain researchers to update and codify pain terminology. 47 Currently, pain is categorized into 3 mechanistic groups which carry distinct clinical and neurobiological features ( Table 1 ). Nociceptive pain is caused by actual or threatened damage to nonneural tissue via activation of nociceptors. Common eye related examples of nociceptive pain include pain related to corneal abrasions, ocular surface inflammation, or acute angle-closure glaucoma. Elimination of the noxious stimulus (e.g., lowering the intraocular pressure in acute glaucoma) or peripherally acting medications that decrease nociception (e.g., proparacaine in corneal abrasion), will relieve nociceptive pain. Neuropathic pain is caused by a lesion or disease in the somatosensory system, including the peripheral and central nervous systems. Neuropathic pain is believed to be the primary mechanism underlying conditions such as herpetic keratitis, post-herpetic neuralgia, and post-LASIK ocular pain. In these cases, injury has occurred to the peripheral nerves; however, neuropathic pain can also arise from injury in the CNS (e.g., thalamic stroke, traumatic brain injury). Treatments often vary in these conditions and may require a combination of therapies directed at the peripheral nerves and/or CNS (e.g., alpha-2-delta ligands). Nociplastic pain, which is our focus, is characterized by altered pain perception that occurs despite the absence of tissue damage that would activate peripheral nociceptors or a lesion of the somatosensory system. 16 Nociplastic pain involves a number of dynamic mechanisms that lead to pain expression. 46 The mechanisms that lead to the development of nociplastic pain are incompletely understood, but CNS changes that are central to pain processing are key. 49 In a top-down mechanistic model, changes in prefrontal and frontal neural circuitry can arise from biological and social triggers including genetic and epigenetic, environmental, socioeconomic stress, and trauma. 41 By contrast, in a bottom-up model, peripheral triggers from nerve or tissue injury, hormones, or ocular or systemic inflammation may drive changes in the CNS that maintain ongoing pain. Therefore, nociplastic pain can occur both in the presence of ongoing nociceptive or neuropathic input or in the absence of an identifiable peripheral cause. 41 The prototypical nociplastic pain condition is fibromyalgia, but it can be present in any chronic pain syndrome. It is important to note that while nociplastic pain can occur in isolation, it can also contribute to pain as part of a heterogenous mixed-pain state with ongoing nociceptive or neuropathic pain, as it does in chronic low back pain, 18 , 19 , 31 and rheumatic disorders. 6 Therefore, nociplastic pain should be viewed on a continuum of both severity and its relative contribution to the pain experience, rather than simply a mechanism that is either present or absent. 95 , 96 Yet, detecting and addressing nociplastic pain is important since the presence of nociplastic pain features have been shown to predict disability. 94 , 95 The clinical features of nociplastic pain ( Table 2 ) are pain duration > 3 months, pain out of proportion to objective signs on clinical examination or testing, pain in multiple body regions (i.e., multisite or widespread pain), presence of other widespread or regional chronic pain conditions (so called chronic overlapping pain conditions [COPC] or primary pain disorders), and associated non-pain CNS-mediated symptoms including fatigue, sleep disturbances, mood disorders, cognitive and memory impairments. 16 COPCs are a group of 10 recognized chronic pain conditions in which nociplastic pain is the predominant underlying mechanism. These individuals may experience pain in different body regions over time. 1 , 21 , 22 , 70 , 89 , 90 , 93 , 99 , 100 The 10 currently recognized COPCs include fibromyalgia, vulvodynia, temporomandibular disorders, myalgic encephalomyelitis/chronic fatigue syndrome, irritable bowel syndrome, urologic chronic pelvic pain syndromes (e.g., interstitial cystitis/painful bladder syndrome), painful endometriosis, chronic tension-type headache, chronic migraine headache, and chronic lower back pain. 57 COPCs are known to coaggregate in individuals and families, and have a strong genetic component. 93 The clinical nociplastic features, such as the presence of non-pain CNS mediated symptoms, have been identified in subgroups of nearly every COPC. 57 The neurobiological features of nociplastic pain include hyperresponsiveness to both pain provoking and innocuous stimuli on quantitative sensory testing (QST) 11 , 16 , 29 – 31 , 33 , 34 , 52 , 92 , as well as altered neuronal activity in CNS sensory processing regions on functional neuroimaging among individuals exposed to innocuous and painful sensory stimuli. 13 , 31 , 33 , 62 , 81 In QST, quantifiable stimuli (e.g., mechanical, thermal) are delivered systematically to measure sensory gain or loss. Multisite and regional hyperalgesia and allodynia, impaired endogenous pain modulation, and amplification of pain perception with repeated painful stimulation (i.e., temporal summation of pain) are characteristic among individuals with nociplastic pain on QST. Individuals with nociplastic pain are also more sensitive to other sensory stimuli, such as the brightness of lights and the loudness of noises. 16 , 27 , 28 , 53 , 75 , 91 Although sensitivity to painful peripheral stimuli could occur via a variety of peripheral and central mechanisms, the sensitivity to multiple sensory stimuli transmitted via cranial nerves to the CNS strongly suggests that the CNS is the primary driver of these phenomena. Furthermore, multiple resting state brain networks are altered and are more connected in nociplastic pain conditions 17 , 36 , 38 , 39 , including the default mode (DMN), salience (SLN), and sensorimotor (SMN) networks. The DMN includes medial prefrontal cortex and posterior cingulate/precuneus anatomic regions. It is involved in thoughts about the self and is typically active during rest. The SLN consists of regions in the insula and anterior cingulate cortex. It is key to directing attention and integrating sensory, cognitive, and emotional information. The SMN consists of primary sensory and motor cortices, integrating motor output in response to sensory input. In general, individuals with nociplastic pain display increased resting state functional connectivity between brain regions that are pronociceptive (e.g., insula and primary somatosensory cortex) and decreased resting state connectivity between brain regions that are antinociceptive (e.g., rostral anterior cingulate and periaqueductal grey). For example, in fibromyalgia patients, greater clinical pain is associated with greater DMN-SLN (insula) connectivity 63 , a neural marker which has also been associated with high scores on a surrogate measure of nociplastic pain (Widespread Pain Index) in patients with rheumatoid arthritis. 6 DMN-insula connectivity is also diminished following a CNS-directed treatment. 37 Additionally, the SLN is altered in nociplastic pain patients, primarily showing increased connectivity between the insula and SMN regions.

Currently, history and physical examination are key to identifying nociplastic pain in the clinic ( Table 2 ). When the history uncovers symptoms of multisite pain and coexisting COPCs, clinicians should evaluate for non-pain CNS mediated symptoms such as insomnia, mood disorders and cognitive changes. Family history may also disclose the presence of chronic pain in immediate family members because nociplastic pain has a genetic component, particularly among younger patients. 15 When combined with a normal eye exam (e.g., “pain without stain”) or pain out of proportion to examination findings, clinicians should be alerted to the likely presence of nociplastic pain. Although optimal treatment of nociplastic pain in patients with COSP is undefined, when the examination reveals peripheral sources of pain, such as features of DE (e.g., decreased tear production, corneal and conjunctival epithelial cell disruption) or other structural causes of COSP initiating appropriate treatments directed at these sources is always the first step; however, poor treatment response to peripherally directed therapies is characteristic of nociplastic pain. For example, in studies of surgeries intended to relieve chronic knee or pelvic pain by addressing presumed peripheral causes, higher scores on the Widespread Pain Index--a self-report measure of the spatial distribution of pain and indicator of nociplastic pain--were associated with decreased responsiveness to surgery. 3 , 8 In patients with COSP with nociplastic pain, response to topical eye drops or procedures (e.g., punctal plugs) will similarly be poor if nociplastic pain is the primary mechanism or incomplete if part of a mixed pain mechanism. This contrasts with nociceptive pain, which is responsive to peripheral therapies, and neuropathic pain in which response to peripherally directed therapies is often more variable. Nonpharmacologic therapies are the cornerstone for nociplastic pain management and these same non-pharmacologic treatments are likely to be essential for addressing nociplastic pain in COSP. 16 , 64 Nonpharmacologic treatment begins with patient education about nociplastic pain and validation of the pain experience by confirming it, naming it, and describing it. 32 The patient-clinician relationship is central to this process. 20 Lifestyle changes that promote sleep hygiene, physical activity, and stress reduction are also key. Evidence is emerging for psychological interventions such as mindfulness-based stress reduction and acceptance-based interventions. Treatment of pain may also reduce the burden of co-occurring non-pain CNS mediated somatic symptoms. One study of patients with fibromyalgia demonstrated that achieving greater than a 50% reduction in pain intensity has been associated with improvement in mood, sleep, and fatigue. 60 Drugs that act on the CNS are often part of a multimodal treatment strategy, although the data are limited. Response to CNS acting medications, however, is not a distinguishing feature of nociplastic pain as response to these medications can be observed in patients with nociplastic pain and neuropathic pain. A number of medications including pregabalin, duloxetine, and milnacipran have received FDA approval for treatment of nociplastic pain conditions such as fibromyalgia but have not been studied in clinical trials including patients with COSP. Cochrane review and network meta-analysis investigating 25 different antidepressants concluded that only duloxetine and perhaps milnacipran (both serotonin and norepinephrine reuptake inhibitors [SNRIs]), have sufficient data to support their use in chronic pain. 7 The average length of the included randomized controlled trials was 10 weeks, so long term efficacy could not be determined. For all other medications, the evidence was of low certainty. Regardless, most pharmacologic therapies including SNRIs, provide only modest benefits for patients with nociplastic pain—an estimated 10–15% beyond placebo-- and are often associated with side effects. 45 , 59 , 60 More traditional analgesics (e.g., acetaminophen) are typically ineffective, and opioids should be avoided. 16 , 64 Thus, nonpharmacologic integrative therapies, such as education, lifestyle changes, psychotherapeutic interventions (e.g., cognitive behavioral therapies), remain the cornerstone of multimodal nociplastic pain management. 16 Clinicians must remember that pain often fluctuates over time due to multiple biological factors (e.g., worsening eye dryness), psychological, and social factors. Therefore, clinicians need to reassess patients and adjust treatments over time to address the current pain triggers.

Emerging evidence suggests that nociplastic pain may be a primary or maintaining mechanism in COSP (e.g., after a nociceptive cause is treated such as dry eye disease), or may be part of a mixed pain mechanism that includes nociplastic in addition to neuropathic and nociceptive components. A number of the clinical and neurobiological features of nociplastic pain have been observed among patients with COSP, a term used in this review to describe interrelated painful symptoms of eye aching, burning, stinging, and irritation that can occur in isolation or co-morbid with numerous ocular conditions, including DE, neuropathic ocular pain, and corneal neuropathic pain (a sub-type of neuropathic ocular pain where a lesion or disease occurs within peripheral corneal nerves). When the top-down conceptual model of nociplastic pain is applied to COSP, it suggests that COSP may arise in some patients as a primary pain condition, similar to fibromyalgia whereby altered or dysfunctional pain processing in the CNS is the underlying cause. Similarly, the bottom-up model would suggest that altered or dysfunctional pain processing in the CNS may maintain pain in COSP, arising as a result of a past or ongoing nociceptive or neuropathic trigger, such as ocular surface inflammation or loss of tear homeostasis in patients with DE. In this section, we will highlight some of these features supporting the presence of nociplastic pain mechanisms in a subset of patients with COSP. As previously noted, COSP is frequently studied within the context of specific diagnoses, particularly DES, which makes an examination of the existing literature for nociplastic pain features challenging. Furthermore, these diagnostic terms (e.g., DES) are applied using criteria that differ between studies. Similarly, the diagnostic term neuropathic ocular pain is widely accepted among eye care providers and used in the literature, but it can lead to confusion when applied within the context of our current understanding of pain mechanisms. It was introduced prior to the 2016 IASP terminology update to distinguish ocular pain arising from injury of the somatosensory system from pain arising from nociceptive mechanisms. In light of our current understanding of pain mechanisms, the diagnosis of neuropathic ocular pain should not be interpreted as implying that the underlying pain mechanism is exclusively neuropathic; nociplastic and even nociceptive mechanisms may co-exist as part of a mixed pain syndrome. Last, a number of the clinical features we will discuss in the following sections are not exclusive to nociplastic pain when considered in isolation. For example, corneal/ocular hypersensitivity can be indicative of nociplastic, neuropathic, or nociceptive pain. Yet, hypersensitivity in the setting of a normal ocular surface examination, multisite or widespread pain (or a diagnosis of COPCs), and poor response to peripherally directed therapies is highly suggestive of nociplastic pain. COSP is often attributed to “dry eye” because of the quality of the pain (e.g., burning or stinging) and/or exacerbation of pain with environmental factors, in addition to the presence of ocular surface signs. Ocular surface signs that may be present on clinical examination among patients with DES include decreased tear stability, decreased tear production, corneal and conjunctival epithelial cell disruption, and ocular surface inflammation. 77 , 97 However, as in other chronic pain conditions, 87 correlations between DES signs and symptoms are low to moderate at best (r 2 <0.16). 5 , 85 Some individuals with DES have significant ocular surface signs with minimal pain, and others have minimal/no signs but experience severe COSP (i.e., sign/symptom discordance) suggesting that the pain is not due to a peripheral cause alone and may be due to the presence of nociplastic pain. Although sign/symptom discordance is not exclusive to nociplastic pain and is often observed in patients with neuropathic pain, symptoms out of proportion to signs should alert clinicians to consider that pain that is not caused exclusively by nociceptive mechanisms. Discordance is defined variably within studies but appears to be relatively common, particularly among patients with COSP associated with DES. In the largest clinical trial to date of moderate-to-severe DES (defined in brief as 2 or more ocular surface signs, OSDI ≥25, dry-eye related symptoms for at least 6 months and use/desired use of artificial tears twice daily for 2 weeks prior to screening), 22.2% (n=119) of participants had symptoms out of proportion to signs. Discordance with signs out of proportion to symptoms was determined based on latent profile analysis to identify patient subtypes based on baseline OSDI, tear break-up time, anesthetized Schirmer test, corneal and conjunctival staining, and meibomian gland dysfunction. 98 In smaller observational cohorts of patients with DES symptoms that defined discordance (more symptoms than signs) by comparing OSDI scores to measures of single ocular surface signs (e.g., Schirmer test) or a composite score of signs, discordance was evenly distributed across the study populations. 67 , 77 Numerous studies have suggested that subsets of patients with COSP have co-occurring COPCs. In a twin study of COPCs, DES (defined on the basis of clinician diagnosis and concurrent use of artificial tear eye drops or gels) was found to co-aggregate with other COPCs. This coaggregation was higher in monozygotic twins than in dizygotic twins, suggesting a genetic susceptibility toward chronic pain in some DES individuals. 86 A systematic review and meta-analysis of 14 studies with over 3 million participants found that individuals with chronic pain conditions we more likely to experience DES symptoms (i.e., COSP) compared to controls and the symptoms were also more severe. 43 Likewise, in a study of over 3 million Veterans, DES frequency (ascertained by International Classification of Diseases, Ninth Revision (ICD-9) codes, including ICD-9 code for sicca syndrome, keratoconjunctivitis sicca, tear film insufficiency, visual discomfort, or pain in or around the eye) increased with the number of chronic co-morbid pain conditions suggesting common underlying mechanisms. 51 Moreover, stronger relationships were observed between patients with DES pain or visual discomfort and COPCs compared to diagnoses causing tear film dysfunction. Furthermore, the presence of some COPCs such as fibromyalgia, and mood disorders have been found to be significantly associated with ocular sign/symptom discordance. 14 , 67 , 77 , 84 In a small study of 48 COSP patients, those with COSP out of proportion to ocular surface signs more closely resembled patients with fibromyalgia (n= 23 fibromyalgia). They had worse mean overall visual quality of life scores (discordant 84.3 [SD8.7] and fibromyalgia 82.5 [SD 13.3]) when compared to concordant patients and healthy controls (concordant 91.7 [SD 4.5] and healthy controls 95.6 [SD 303]). 77 The presence of non-pain CNS mediated symptoms, such as mood and sleep disorders, have been associated with COSP. In a recent meta-analysis, DES (based on “well defined criteria” inclusive of both signs and symptoms, except 2 studies using ICD9 codes) was associated with a significantly increased prevalence of depression (summary odds ratio [OR]=2.92, 95% CI: 2.13–4.01, P<0.001) and anxiety (OR=2.80, 95% CI: 2.61–3.02, P<0.001). 88 Depression scores and anxiety scores overall were also higher in DES patients than controls. While increased depression and anxiety could be due in part to poorly controlled peripherally mediated pain (e.g., ocular surface inflammation) or impaired visual function, studies assessing both ocular surface signs and symptoms suggest mood disorders may be a non-pain CNS mediated symptom indicative of underlying nociplastic pain. In a prospective study of 154 Veterans (91% men) with COSP, a Dry Eye Questionnaire 5 (DEQ5) score ≥6, and normal eyelid and corneal anatomy, participants with more COPCs had more severe COSP and significantly greater PTSD and depression scores on standard questionnaires. 24 Likewise, in a cross-sectional study of 187 Veterans, those with DES symptoms (DEQ5≥6) and high pain intensity had significantly more insomnia (at least moderate), compared to low pain intensity and control groups. 26 In a large population based cohort study, nearly 45% of patients with DES symptoms (defined as the presence of both dryness and irritation either ‘constantly’ or ‘often’) had poor sleep quality as measured by the Pittsburgh Sleep Quality Index compared to nearly 25% of controls. 56 However, rigorous phenotyping studies among more representative populations of patients with COSP and using validated patient-reported outcome measures (PROMs) of multisite pain, COPCs, and some non-pain CNS-mediated symptoms (e.g., fatigue, cognitive/memory impairments) have not yet been examined. Although only a few studies have been performed using QST in patients with COSP, the sensory features of nociplastic pain including multisite and regional hyperalgesia and allodynia, impaired endogenous pain modulation, and amplification of pain perception, appear to be present in some patients with COSP. A cohort of 1635 women in the TwinUK registry with DES (defined as a diagnosis of DES by a clinician, a prescription of artificial tears, and/or symptoms of DES ≥ 3 months) showed increased pain sensitivity compared to controls with significantly lower heat pain thresholds at a remote site on the forearm. 83 Similarly, pain intensity ratings reported at cold and hot thresholds on the forehead and forearm were correlated with sign/symptom discordance in a sample of 326 veterans (92% men), such that increased pain sensitivity was associated with greater discordance. 67 Prolonged aftersensations of pain evoked by noxious hot and cold stimuli were also significantly correlated with sign/symptom discordance scores, suggesting that some patients with COSP have decreased descending pain inhibition contributing to pain amplification. 67 In a separate study of 118 Veterans with DES (symptoms and signs (none to severe])and no overt eyelid or corneal abnormalities), temporal summation on the forearm, which suggests amplified CNS pain perception remote from the eye, was correlated with burning ocular pain and greater corneal sensitivity. 25 Topical anesthetics, such as proparacaine, rapidly dampen peripheral nociceptive and corneal afferent input from the ocular surface. Therefore, pain should be significantly reduced or eliminated in people with peripherally mediated ocular surface pain. By comparison, pain arising in the CNS or referred from a remote site (e.g., occipital neuralgia or dental pain) should not respond to topical anesthetic. Because neuropathic pain can arise from injury to the peripheral or central nervous system, responses to topical anesthetic are more variable. A cross-sectional study of 224 veterans (91% men) with COSP found that those with persistent pain following topical ocular anesthetic had higher eye pain intensity scores without any significant difference in most ocular signs between responders and nonresponders. 14 Individuals with residual pain following instillation of topical anesthetic have also demonstrated allodynia on QST at sites remote from the eye 14 suggesting widespread, amplified pain perception, a key feature of nociplastic pain. Few functional brain studies have been performed in COSP, all with small sample sizes, although they generally show increased pro-nociceptive activity or connectivity in brain regions similar to other nociplastic pain conditions. In one such study, 8 DES patients with photophobia (at least 1 positive response on 4 photophobia screening questions, OSDI>12, ≥1 ocular surface signs) and 11 healthy controls were exposed to light stimulation during fMRI. 80 Patients had greater activation in visual cortex and stronger connectivity between visual areas and SLN brain regions, similar to other conditions such as tinnitus, hyperacusis, and pain. 42 Similarly, in a study of 8 patients with COSP (pain ≥ 6 months) and 8 healthy controls, pain ratings correlated more with light-evoked activation in pain-related areas within the brainstem (trigeminal areas), primary somatosensory cortex, anterior mid-cingulate cortex, and insula when compared to controls. 9 Application of topical anesthetic among patients with COSP resulted in decreased activation within the somatosensory cortex and anterior mid-cingulate cortex, but not the visual cortex or insula. The decrease in some pro-nociceptive regions (e.g., somatosensory cortex), but not others (e.g., insula), may be suggestive of mixed pain mechanisms. Likewise, the clinical pain responses to anesthetic were heterogenous. Additional small studies have found increased activity in visual cortex and less activity in prefrontal DMN and dorsal attention network regions during resting state, changes in white matter pathways, 54 increased gray matter volume in the insula and precentral gyrus in females with COSP 44 and decreased connectivity between the cerebellum and thalamus. 68 In vivo confocal microscopy (IVCM) is a noninvasive imaging tool allowing for quantitative analysis of ocular surface structures, including the corneal nerves. Studies have demonstrated decreased sub-basal corneal nerve fiber density and presence of microneuromas compared to healthy controls, often interpreted as supporting a peripheral neuropathic mechanism of COSP, similar to patients with DE secondary to Sjogren syndrome. 55 , 66 For example, in a study of 14 people with COSP (continuous severe ocular pain ≥ 1 year, minimal or no ocular surface signs, and no response to topical treatment) compared to 7 healthy controls, individuals with COSP had lower sub-basal nerve densities (and microneuromas in stromal nerves), but there were no significant differences in corneal sensation using Cochet Bonnet esthesiometry between groups. 71 More microneuromas were associated with significantly less pain following topical anesthetic. Presence of microneuromas have also been associated with photophobia. 2 Although identifying corneal nerve fiber changes such as these, might suggest a peripheral neuropathic component to COSP, there are also substantive data suggesting that in nociplastic conditions, such as fibromyalgia, there are decreases in intraepidermal nerve fiber density. Preclinical data suggest these types of changes may represent neuroplasticity attributable to redacted peripheral afferent nerve fibers from a primary nociplastic mechanism. A proof-of-concept study demonstrated that an induced increase in endogenous glutamate in the bilateral insula of rats led to sustained pain behaviors (e.g., decreases in mechanical paw withdrawal thresholds, increased aversion to noxious mechanical stimulation) and decreased intraepidermal nerve fiber density in the paw. 40 Just as there are decreases in the size of most of the brain regions involved in pain processing in individuals with nociplastic pain conditions, these decreases in peripheral nerve density may also represent neuroplasticity. 10 , 40 In support of this hypothesis, Shtein and coworkers found significantly decreased nerve fiber density in the sub-basal cornea of patients with discordant COSP similar to fibromyalgia “positive controls”. 77 When viewed through the lens of our current understanding of pain mechanisms, these studies indicate that a subset of COSP individuals likely have clinical and neurobiological features of nociplastic pain. In some patients, nociplastic pain may be the primary mechanism, but in many cases, it part of a mixed pain syndrome with other nociceptive and neuropathic features. To date, no studies have comprehensively assessed the established clinical phenotypic and neurobiological features of nociplastic pain in COSP, particularly using large cohorts’ representative of patients with COSP. Future research should focus on collection of multimodal QST data, fMRI data, and validated patient-reported outcome measures of multisite pain, COPCs, and non-pain CNS-mediated symptoms which are now common across pain research and routinely deployed within national pain research consortia. This type of approach has been applied to the study of chronic low back pain and chronic pelvic pain arising from interstitial cystitis and chronic prostatitis, both of which are funded by the National Institutes of Health. 12 , 65 It would also allow for a more direct comparison of COSP to other COPCs and uncover opportunities to extend effective multimodal therapeutic strategies to patients with COSP. Furthermore, there are no validated tests to identify patients with nociplastic pain, but diagnostic frameworks have been proposed for patients with chronic musculoskeletal pain and chronic visceral pain syndromes. Developing and validating similar clinical tools or novel tools to aid clinicians in detecting nociplastic pain in the clinic among patients with COSP will be central to reducing pain and improving quality of life.

COSP is common, burdensome, and our current therapeutics fail to adequately treat many patients. We must shift our attention from focusing on COSP as a manifestation of an underlying disease only, such as DE, to a diagnosis in its own right. Clinical and neurobiological studies support the concept that a subset of patients with COSP have nociplastic pain as the primary or sustaining pain mechanism, similar to other chronic pain conditions. Although rigorous and comprehensive mechanistic studies are critical to further defining the role of nociplastic pain among patients with COSP, clinicians can apply existing principles of nociplastic pain management to patients suffering with COSP encountered in clinic. Nociplastic pain must be considered as a primary mechanism or part of a mixed pain mechanism when clinical signs of pain occur out of proportion to ocular surface signs, numerous non-pain CNS mediated symptoms are present, and pain is regionally or widely distributed or multiple chronic pain conditions are present (or have occurred previously). Continuing to rely on peripherally directed therapy for these patients, will not provide adequate relief. Multimodal integrated therapies are needed among which non-pharmacologic interventions are the cornerstone. Ultimately, successful future treatment strategies for COSP will depend not only on the success of addressing relevant nociceptive and neuropathic pain, but also the degree to which nociplastic pain can be identified and managed.

Chronic ocular surface pain (COSP) refers to inter-related symptoms such as eye burning, aching, and irritation, and is a leading cause of eye care visits in the US. 76 COSP can occur as an isolated condition or it can be co-morbid with numerous ocular disorders including dry eye (DE), allergic conjunctivitis, and structural ocular abnormalities. Although the exact prevalence of COSP is unknown, over 5% of people are estimated to experience these interrelated symptoms often or all of the time either in isolation or associated with another ocular disorder (e.g., dry eye syndrome [DES]). 4 , 69 , 73 , 74 , 79 Because the symptoms may be relentless and lifelong, patients with severe COSP often experience decreased quality of life 61 , 72 similar to those with an immobilizing hip fracture or moderate/severe angina, 58 decreased visual functioning, 50 , 77 and have higher odds of suicidal ideation. 82 Treatments for COSP are largely aimed at addressing peripheral sources of pain, including restoring tear film homeostasis, reducing ocular surface inflammation, and improving epithelial disruption. While this is the first line of treatment when objective signs of ocular surface or corneal nerve injury exist, in patients with COSP response to these peripherally-directed treatments (e.g., artificial tears, cyclosporine A) are variable with higher pain intensity associated with lower treatment responses. 23 , 78 Interestingly, conventional analgesics that target peripheral sources of pain have likewise been demonstrated to have a minimal impact on other regional chronic pain conditions, such as temporomandibular disorder and interstitial cystitis/bladder pain syndrome. 46 A potential explanation for these observations is that, in a subset of patients with COSP, individuals have amplified and/or dysregulated neural signaling and sensory processing within the central nervous system (CNS). As in other chronic pain conditions, this might be the pathogenic mechanism primarily responsible for maintaining pain - a phenomenon now referred to as nociplastic pain. 16 , 35 , 48 , 75 In the newest International Classification of Diseases these same nociplastic pain conditions are referred to as “primary pain” since the pain is the problem, not a disease causing damage or inflammation leading to pain. In this type of pain, therapeutic strategies that target the CNS are key to delivering pain relief. Our objective is to provide an overview for eye care clinicians of nociplastic pain in the context of more familiar pain phenotypes and to delineate the emerging evidence for the presence of nociplastic pain among some patients with COSP. We will also highlight gaps in our current understanding of nociplastic pain in COSP and provide clinicians with specific tools that may aid in the assessment and management of nociplastic pain in their clinics.