Ocular surface pain is a frequent cause of visits to an eye care provider
and has a substantial impact on healthcare cost, yet a complete understanding of its
causative factors and tools for diagnostic workup are notably missing in many eye
clinics. The cornea has the densest sensory innervation in the human body and has the
potential to be a powerful producer of pain. Pain can manifest as a result of a noxious
stimulus or disruption in the ocular surface anatomy (nociceptive pain), or it can
result from abnormalities in the ocular surface neurosensory apparatus itself
(neuropathic pain). Novel advances in neurobiology have sought to differentiate the two
entities, particularly to identify when chronic dry eye symptomatology is driven by
neuropathic ocular pain. In this review, we seek to provide an overview of the
prevalence, physiologic factors, and management of ocular surface pain
complaints.
Ocular surface pain is a common cause of visits to eye care
practitioners, frequently presenting within the scope of other ocular
conditions such as dry eye, with substantial implications on global
quality of life and healthcare cost.
Ocular surface pain may arise directly from tissue damage at
the ocular surface or from changes to peripheral or central nerves in
the ocular surface sensory pathway.
The trigeminal subnuclei have emerged as significant players
in the modulation of ocular surface sensations, as explored in several
animal models.
Several risk factors have been associated with ocular surface
pain, including Sjögren’s, graft versus host disease, migraine,
fibromyalgia, refractive surgery, and environmental
conditions.
The treatment of refractory chronic ocular surface pain
should address the underlying contributors in an individual patient.
In some cases, the use of therapies that modulate nerve function
should be considered.
Introduction
Interest in ocular surface pain has intensified in recent years, given that
it is a common reason for presentation or referral to an eye care provider, has immense
cost implications, and impacts quality of life (QoL). A detailed pain assessment is an
essential part of a comprehensive eye examination. Subjective pain descriptors may
include dryness, discomfort, grittiness, itchiness, burning, stabbing, shooting, or
aching pain [1], and these conditions may
occur spontaneously or be exacerbated by environmental insult, such as wind, light, or
temperature changes. In the setting of an acute trauma, surgery, or infection, pain is
ordinarily transient, and resolution of pain promptly follows treatment of the
underlying condition. However, at times, pain may persist, either due to continued
stress on the ocular surface or to nerve abnormalities, or both [2].
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The International Association for the Study of Pain (IASP) defines pain as
“an unpleasant sensory and emotional experience associated with actual or potential
tissue damage” and pain is commonly stratified into two broad groups—nociceptive and
neuropathic pain. Nociceptive pain refers to direct activation of nociceptors due to
actual or threatened damage to non-neural tissue and implies an intact somatosensory
nervous system [3]. In the eye, this is
typically associated with transient pain following injury, surgery, or infection.
Neuropathic pain is caused by a lesion or disease of the intrinsic somatosensory nervous
system, often in the absence of other tissue injury. Investigation into the
pathophysiology of neuropathic pain is ongoing in several prevalent disease states,
including fibromyalgia, irritable bowel syndrome, vulvodynia, interstitial cystitis, and
atypical facial pain disorders [4].
Interestingly, many individuals with these co-morbidities also have chronic ocular
surface pain [5, 6]. In fact, similar to these chronic pain conditions
outside the eye, neuropathic ocular pain (NOP) often presents with pain out of
proportion to clinical signs.
The aim of this review was to provide eye care providers with a detailed
overview of ocular surface pain, with a focus on epidemiology, neuro-pathophysiology,
diagnosis, and treatment. Irregularities in other parts of the eye, such as neuritis,
scleritis, and acute glaucoma, may also be associated with pain, but are beyond the
scope of the current review. Articles for this review were compiled from the National
Library of Medicine MEDLINE database, with a search in PubMed with the keywords “ocular
surface pain”; searches were limited to articles written in English. This article is
based on previously conducted studies and does not contain any studies with human
participants or animals performed by any of the authors.
Epidemiology
Information on the epidemiology of ocular surface pain is often hidden
within the literature on dry eye (DE), as one of the major symptoms of DE is ocular
surface pain, characterized not only as dryness, but also as discomfort, burning,
itchiness, irritation, and photophobia (evoked pain to light), to name a few
[1, 7]. Dry eye symptoms, including pain, are a leading cause of visits to
eye clinics and ophthalmic healthcare costs [8]. Ocular surface pain has a negative impact on QoL, impacting both
physical and mental functioning [9]. It has
been associated with insomnia [10], poor
coping mechanisms [11], and impaired social
functioning [7], and the implications
stretch to activities of daily living, such as reading, driving, and computer function,
in addition to decreased occupational productivity and missed work [7]. Fortunately, recent advancements in the
understanding of the pathophysiology of neurobiology of ocular surface pain may lead to
novel therapies to alleviate individual and societal burden.
Prevalence
Symptoms of Ocular Surface Pain in the General Population
As mentioned in the preceding section, data on the prevalence of
ocular surface pain is generally extrapolated from the DE literature. Several
population-based studies have investigated the prevalence of subjective ocular
surface symptoms. The Blue Mountains Eye Study collected door-to-door data asking
residents to complete a questionnaire on self-reported ocular symptoms. Of the
1174 Australian residents aged 49 years and older who responded, a positive
response to mild, moderate, or severe grittiness was reported by approximately 25%
and eye discomfort was reported by approximately 30% [12]. Another population-based study of 926
volunteer Melbourne residents asked individuals to self-report and grade ocular
discomfort, foreign body sensation (FBS), itching, dryness, and photophobia. In
this group, mild, moderate, or severe discomfort was reported by 32% of
individuals, FBS by 26%, itching by 40%, dryness by 17%, and photophobia by 50%
[13].
A high prevalence of ocular pain symptoms was also found in the UK.
One study utilizing the TwinsUK adult registry extrapolated data from the Ocular
Surface Disease Index (OSDI), a 12-item scale that is used to assess DE syndrome
(range 0–100) [14]. The first three
questions of the OSDI represent the ‘ocular symptoms pain domain’ as they ask
about eyes that are sensitive to light (question 1), eyes that feel gritty
(question 2), painful or sore eyes (question 3), with frequency graded from 0
(never) through 4 (all of the time) during the past week [15]. In this cross-sectional study, 689 women
completed the OSDI, of whom 17.1% (n = 118)
reported OSDI pain symptoms in the past week, as calculated by a sum score of ≥ 3
for the first three OSDI questions [14].
Similar data has been found in the USA. Two large-scale surveys
evaluated the prevalence of ocular dryness and irritation in US populations of
female and male healthcare professionals. Of the 36,995 women participating in the
Women’s Health Study survey (ages 45 through 84 years), dryness was experienced
constantly in 381 (1.0%), often in 2109 (5.7%), and sometimes in 10,474 (28.3%).
In this same group, symptoms of irritation were reported constantly in 207 (0.6%),
often in 2102 (5.7%), and sometimes in 18,901 (51.1%) [16]. The Physicians’ Health Studies surveyed
25,444 male healthcare workers aged > 50 years. Dryness was reported constantly
in 204 (0.8%), often in 924 (3.6%), and sometimes in 4716 (18.5%); irritation was
reported constantly in 126 (0.5%), often in 1050 (4.1%), sometimes in 10,622
(41.8%) [17]. A comparison of data
between the two studies reveals a higher frequency and severity of ocular dryness
and irritation in women than in men [16‐18]. In another US population-based study, 2482 volunteers aged
65 to 84 years in Salisbury, Maryland were asked about self-reported frequency of
dryness, grittiness, and burning. Among these individuals, 22% reported dryness,
33% grittiness, and 25% burning sometimes, often, or all the time [19].
The above numbers were generated by studying the general population
and not individuals seeking eye care. Thus, the results of these studies highlight
that a significant proportion of the general population has some degree of ocular
surface pain, some or all of the time.
Risk Factors and Associations
Acute ocular surface pain commonly occurs due to local tissue injury in
the setting of trauma, surgery, and infection [2, 20]. Many factors
have been associated with chronic ocular surface pain, including congenital or
acquired anatomical abnormalities of the eyelids (i.e., entropion, ectropion) and
conjunctiva (i.e., conjunctivochalasis, pterygium), and systemic, iatrogenic, and
environmental factors [21‐23].
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Considering systemic associations, immune disorders have been most
closely linked to chronic ocular surface pain, namely, Sjögren’s syndrome and
graft-versus-host disease (GVHD). Sjögren’s syndrome is an autoimmune disease in
which lymphocytic infiltration injures the lacrimal gland, leading to disruptions in
the tear film [24]. In a study of 224
individuals with primary Sjögren’s syndrome in Nantong, China, the mean overall OSDI
score (0–100) was 25, with an average ‘OSDI symptoms domain’ score of 29 (calculated
using the first five questions of the OSDI that include pain and visual complaints,
range 0–100). The study further grouped individuals by location and found higher OSDI
scores in inpatients (n = 127) versus outpatients
(n = 97) (30 vs. 18; p < 0.001) [25]. In
another study of 18 individuals with primary or secondary Sjögren’s syndrome, OSDI
symptom severity negatively correlated with lissamine green corneal staining
(r = − 0.43, p = 0.01) [26],
suggesting a reduction in reported symptoms with increasing ocular surface damage and
providing evidence for discrepancies between ocular surface pain and DE signs
[27, 28]. Chronic graft-versus-host disease (cGVHD) is also associated
with chronic ocular surface pain. cGVHD commonly occurs after hematopoietic stem cell
transplantation (HSCT). In 136 individuals who underwent HSCT and who did not have a
prior diagnosis of DE, mean OSDI scores increased post- versus pre-HSCT (20 vs. 2.6;p < 0.001), with the most common primary
complaints being dryness/FBS (n = 27), blurred
vision (n = 20), and photophobia (n = 6) [29].
These above studies point to chronic immune activation as one cause of chronic ocular
surface pain.
Chronic non-ocular pain conditions have also been linked to chronic
ocular surface pain. For example, individuals with migraine frequently report
symptoms of ocular discomfort [32]. In a
study of 250 individuals at the Miami Veterans Affairs Hosptial, ocular symptom
profiles were compared between individuals with and without migraine (31 vs. 219
individuals, respectively). Those with migraine had a higher intensity of ocular
surface pain compared to controls (mean ± standard deviation [SD]: OSDI 54 ± 22 vs.
36 ± 23, p = 0.0001; Neuropathic Pain Symptom
Inventory modified for the eye [NPSI-Eye] [33] 39 ± 23 vs. 22 ± 20, p = 0.0001) but similar ocular surface findings [34]. Other pain conditions linked to ocular
surface pain include chronic muscle/back pain, fibromyalgia, and chronic pain
syndromes (CPS) [27, 35, 36]. In a German study of 90 individuals who were asked to report
eye pain on a numerical rating scale (NRS) with a range of 0 to 10, 44 of 66 (67%)
individuals with fibromyalgia reportred a mean eye pain rating of 2.6, and 15 of 24
(63%) individuals with chronic musculoskeletal pain reported a mean eye pain rating
of 1.8 [36]. The most frequent eye pain
descriptors were itchiness (~ 60%), annoying (~ 50%), and tiring (~ 45%). These
numbers were presumed to be higher than the frequency of ocular surface pain in the
general German population [36]. In a US
study, 154 individuals were clustered into groups based on number of chronic
non-ocular pain conditions. ‘High CPS’ (n = 97)
was defined as ≥ 3 conditions and ‘Low CPS’ (n = 57) was defined as 0–2 conditions. The High CPS group reported
significantly worse ocular surface pain over the prior week compared to the Low CPS
group (NRS 0–10: 4.5 vs. 2.9; p < 0.0005). In
addition, the High CPS group reported a higher intensity of neuropathic pain-like eye
symptoms compared to the Low CPS group, assessed using the NPSI-Eye (29 vs. 19;p = 0.006) [6]. The above data reinforce the notion that chronic ocular surface
pain can co-exist with a number of non-ocular pain conditions.
Other systemic conditions associated with chronic ocular surface pain
include trigeminal neuralgia, benign essential blepharospasm (BEB), small-fiber
polyneuropathies, diabetic neuropathy, and chemotherapy and radiation [37]. For example, trigeminal neuralgia (TN) is a
chronic pain condition that presents with craniofacial pain in the distribution of
the trigeminal nerve. TN is characterized by brief, sharp electric-shock-like
paroxysmal pain arising from one or more trigeminal nerve branches (V1, V2, or V3).
Attacks are commonly initiated by mild mucocutaneous stimulation—such as brushing
teeth or chewing motion—in the affected nerve field, known as the trigger zone. Most
cases are primary or idiopathic, although intracranial compression and traction are
known secondary causes. Although TN most commonly presents with pain in the V3 region
(jawline/lower lip area), it can present with pain at the level of V1 and the corneal
surface [37‐39]. BEB is a
condition characterized by abnormal blinking or spasms of the eyelids that is
frequently associated with ocular surface symptoms. In a prospective case series, 40
individuals with DE (Dry Eye Workshop severity grading score ≥ 1 [30]) and BEB were compared to 40 individuals with
DE alone and 40 controls. Individuals with DE and BEB reported significantly higher
DE symptoms via the OSDI (35 ± 7) compared to individuals with DE alone (19 ± 3;p = 0.002) and healthy controls (~ 9 ± 1;p < 0.001) [31]. These data demonstrate that BEB may be an independent
contributor to ocular surface pain.
Iatrogenic factors, such as chronic glaucoma medication use
[40] and refractive surgery
[41], have also been associated with
chronic ocular surface pain. In a cross-sectional study of 62 predominantly male
Miami veterans with glaucoma, individuals using three or more glaucoma medications
reported a higher incidence of shooting pains compared to those on less than three
medications (28% vs. 4%, p = 0.03). Patients on
three or greater topical glaucoma drops were also more likely to experience ocular
dryness (67% vs. 38%; p = 0.04) and itchiness (74%
vs. 44%; p = 0.02) than those on fewer medications
[42]. Chronic ocular surface pain has
also been associated with refractive surgery [43]. Dry eye symptoms are common in the first month post
photorefractive keratectomy (PRK) [41]
or laser in-situ keratomileusis (LASIK), typically with resolution over the following
months, according to the Patient Reported Outcomes With LASIK (PROWL) study
[44]. In the PROWL-1 study, the mean
OSDI of 215 patients was significantly less at the six-month post-op period compared
to pre-procedure baseline (8 vs. 14, p < 0.001)
[44]. However, rare cases have been
documented of persistent refractory ocular surface pain, light sensitivity, and
visual difficulty after surgery, often in the absence of ocular surface signs or
other triggers [45, 46]. These cases suggest that chronic ocular
surface pain can develop after refractive procedures.
Environmental factors have also been associated with ocular surface
pain, particularly exposure to gaseous air pollution [47, 48]. In a study of
55 healthy volunteers in Sao Paulo, Brazil, subjects kept a nitrogen dioxide
(NO2) passive monitoring system beside them for 1 week as a
proxy for exposure to air pollution and completed symptom questionnaires. Total daily
NO2 exposures were categorized into four quartiles (Q1–Q4)
of increasing daily exposure. A dose-dependent pattern was found between daily
NO2 exposure and OSDI (p = 0.01), with a mean OSDI of approximately 8 for Q1, approximately 20
for Q2, approximately 22 for Q3, and approximately 30 for Q4. In addition, symptoms
of ocular irritation were found in 38.5% of individuals in Q1, 64% of those in Q2,
71% of those in Q3, and 93% of those in Q4. Similar findings have been described in
the setting of ozone exposure [49].
These data suggest associations between exposures to noxious environmental insults
and ocular surface discomfort [48].
The results of these studies substantiate associations between several
systemic conditions, iatrogenic therapies, and environmental exposures with chronic
ocular surface pain.
Anatomy, Physiology, and Pathophysiology
The pathways of ocular surface pain involve both peripheral and central
nerves [20]. The peripheral nerves arise
from the richly innervated cornea and ocular surface. Free nerve endings within the
superficial corneal epithelium play an important role in the detection of environment
stimuli but are susceptible to damage [50,
51]. The cornea contains different types
of nociceptive (or pain) fibers, or nociceptors, encompassing all peripherally located
neurons preferentially sensitive to noxious stimuli. These neurons demonstrate dynamic
stimulus–response behavior to prolonged stimulation [52]. With the assistance of animal studies, explorations into the
neurobiology of the corneal sensory pathways (referring to the sum network of peripheral
and central neurons involved in the processing and modulation of ocular surface
sensation) have attempted to clarify the role of primary (peripheral) and second- and
third-order (central) neurons in the pathophysiology of ocular surface pain. Studies in
animals have broadened our understanding of different corneal nociceptive fiber types
[53], nerve terminal ion channels
[20], and sensory interpretation of the
trigeminal nucleus [54, 55].
Corneal Neuroanatomy and Physiology
The cornea is richly innervated with A-delta and C-fiber primary
afferents, which are branches of the nasociliary nerve, itself a branch of the
ophthalmic division of the trigeminal nerve, known as CN V1 (first division of fifth
cranial nerve); thus, the somas of these corneal nociceptors lie in the trigeminal
ganglion [56‐58]. Nasociliary
nerve branches enter the peripheral cornea radially, losing their myelin sheath at
approximately 1 mm from the limbus, before migrating anteriorly to penetrate the
Bowman’s layer and forming the subbasal nerve plexus [37, 56, 58]. Nociceptive free nerve endings are intimately
bound to the epithelial cell borders, even those of apical layers, thereby explaining
the ability of a variety of peripheral noxious stimuli (i.e., fumes, abrasions) to
cause ocular surface pain [50].
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Different nociceptor fibers respond to different environmental stimuli
and include mechanoreceptors (~ 20% of total corneal sensory nerves), polymodal
receptors (~ 70%), and cold receptors (~ 10%) [59]. As reviewed by Belmonte and Gallar, mechanoreceptors are
responsible for the sharp pain felt upon mechanical stimulation, such as an object
contacting the cornea, and are the fastest conductors of the three types of
receptors. Polymodal receptors respond to mechanical, thermal, chemical, and pH
changes. The aptly named cold nociceptors transmit information related to drops in
temperature, for example, in evaporative cooling, and also changes in tear osmolarity
[53, 60]. Pricking pain is most associated with mechanoreceptors,
burning/stinging pain with polymodal receptors, and dryness with cold receptors
[20].
Specific proteins and channels help identify these various nociceptors;
these include Piezo2 in the cell body of the trigeminal ganglion and terminal nerve
endings of corneal mechanoreceptor afferents [61]; TRPA1 and TRPV1, ion channels that respond to chemical and
thermal changes at the terminal nerve endings of polymodal neurons; and TRPM8, an ion
channel which senses evaporation on the terminal nerve endings of thermoreceptors
[20, 62]. Expression of these channels is influenced by reactive oxygen
species, lipid peroxidation products [20], and local inflammatory mediators (i.e., adenosine triphosphate,
prostaglandins, matrix metalloproteinase 8, bradykinin, histamine, immune cell
cytokines) [63], neurotrophic factors
(i.e., nerve growth factor) [64], and
neuropeptides (i.e., calcitonin gene-related peptide [CGRP], substance P)
[20, 56, 65].
Corneal Primary Afferent Pathophysiology
The IASP defines sensitization as the “increased responsiveness of
nociceptive neurons to their normal input, and/or recruitment of a response to
normally subthreshold inputs” [3].
Several studies have found that peripheral nociceptors can become sensitized when
exposed to a variety of insults. Inflammatory damage, noxious stimuli, and
hyperosmolarity directly activate corneal nociceptors, with accompanying changes in
terminal ion channel expression and activity through gene expression, cytosolic
signaling, and transcription factors. These changes are characterized by reduced
activation thresholds and consequently increased excitability [66, 67]. This phenotypic change at the level of the corneal nociceptor
or first-order neuron, though potentially reversible, is termed peripheral
sensitization.
Neural responses and changes in the firing pattern of peripheral
nociceptors have been recorded in response to particular environments. One study
evaluated cold thermoreceptors and polymodal nociceptor nerve terminal impulse (NTI)
activity in mice following exposure to solutions of differing osmolality
(325–1005 mOsm/kg) as well as to an “inflammatory soup” solution (bradykinin,
histamine, prostaglandin E2, serotonin, and ATP) to mimic
inflammatory conditions in vivo [68]. At
a constant basal corneal temperature of 33.6 °C, NTI activity was significantly
increased in cold thermoreceptors in a linear relationship to osmolality (0.34 imp
per second/10 mOsm) once osmolality surpassed 340 mOsm. On the other hand, polymodal
nociceptors in increasingly hyperosmolar exposures only activated with
hyperosmolarities of ≥ 600 mOSM and then in a nonlinear, irregular fashion
characterized by flattened NTI waveform shapes. In the same study, exposure to an
“inflammatory soup” in iso-osmolal saline at 33.6 °C significantly increased
polymodal receptor NTI frequency (from 0.10 to 0.19 imp per second; p = 0.003), with no further increase in NTI activity
following osmolality increases. These results suggest that cold thermoreceptor
activity is more influenced by tear osmolality and polymodal nociceptors by
inflammatory mediators [68]. Both
elevated osmolarity and the presence of inflammatory mediators are often present on
the ocular surface of humans with tear abnormalities.
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Studies have also reported that corneal nociceptors undergo a change in
function following surgical injury. In a rat model of unilateral lacrimal gland
removal, tear production decreased by 35% and spontaneous blink rate increased
fourfold at 1 week after surgery compared to baseline [69]. Menthol application (which activates cold thermoreceptors)
evoked a 1.4-fold greater peak neuronal firing frequency in animals with removed
lacrimal glands compared to controls (p < 0.05). In a similar manner, measurements of neuronal firing
activity in response to rising temperatures were used to determine the cooling
threshold (defined as baseline activity plus 3 standard deviations); the cooling
threshold was also significantly higher (31.5 vs. 29.9 °C; p < 0.05) [69]. This
study provides evidence that changes in ocular surface conditions, such as in aqueous
tear deficiency, result in phenotypic changes in corneal nociceptor response and
sensitivity.
These experimental models provide valuable insight into the normal and
pathologic physiology of the corneal neurosensory system. The studied models
replicate several facets of human disease, including aqueous tear deficiency and
ocular surface inflammation. A limitation in animal models is that pain cannot be
directly assessed. However, secondary markers of pain have been studied as a proxy
for subjective symptoms. Eye wiping, or the purposeful wiping of the face by the
ipsilateral forelimb, is one such test for acute ocular irritation-related behavior
in rats. In a study of eye wipe behavior in rats, drops of NaCl of varying
concentrations (0.15, 1, 2, 3, 5 M) placed onto one eye resulted in a linear dose
response relationship with eye wipes within the next 30 s (F = 24.96, p < 0.01)
[70]. Further, treatment with
10 mg/kg morphine completely eliminated eye wipe behavior in rats given 5 M NaCl,
while lower morphine concentrations (1, 2, 4, 8 mg/kg) resulted in dose-dependent
reductions in eye wipes [70]. Taken
together, these studies suggest that abnormal tear composition, such as elevated
osmolarity, can cause ocular surface pain.
Central Nerves in the Ocular Sensory Apparatus
The cell bodies of corneal pain receptors are located in the trigeminal
ganglion, with fibers from the first-order trigeminal nerve synapsing in the
trigeminal subnucleus caudalis/upper cervical transition zone
(Vc/C1-2) as well as the subnucleus interpolaris/subnucleus
caudalis (Vi/Vc) [50]. Second-order
axons travel from the spinal trigeminal nuclear complex, decussate, and terminate in
the thalamus alongside contralateral spinothalamic fibers. Third-order neurons carry
information from the thalamus to precisely localized areas of the primary
somatosensory cortex [50, 71] (Fig. 1). There is also an important component of pain modulation
originating from the descending pathways of the limbic system, midbrain, and
thalamus; descending signals travel through periaqueductal grey to the brainstem,
modulating pain signals and continuing to the trigeminal nuclear complex
[50, 56].
Fig. 1
A simplified depiction of the ocular surface sensory pathway.
Neuronal cell bodies of corneal nociceptors are located in the trigeminal
ganglion. These first-order neurons synapse at the trigeminal subnucleus
caudalis/upper cervical transition zone and the subnucleus
interpolaris/subnucleus caudalis. Second-order neurons project from
trigeminal subnuclei to the thalamus, and third-order neurons terminate
in the primary somatosensory cortex and other cortical areas. The
thalamus also projects descending inhibitory fibers that are involved in
neural pain modulation
×
Central Nerve Pathophysiology
According to the IASP, central sensitization refers to the “increased
responsiveness of nociceptive neurons in the central nervous system to their normal
or subthreshold afferent input” [3].
Physiologic changes in central neurons that define sensitization include reduced
activation thresholds and increased excitability. These changes can explain why
ocular surface pain is often disproportionate to ocular surface pathology and largely
unaffected by topical treatments [56].
Many factors can lead to changes in central neurons, including persistent peripheral
nociceptive traffic and surface inflammation [72, 73], abnormalities
in descending inhibitory control [67],
or changes in local circuit neurons and microglia [74], among other proposed mechanisms. Several experiments have
demonstrated that central nerve changes can occur in the corneal sensory
pathways.
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Trigeminal Subnuclei in Rat Models
In one animal model, rats were exposed to ultraviolet irradiation
(UVR), which produced a phenotype of photokeratitis, including signs of scleral
hyperemia, corneal opacities, and pupil dilation, hours after irradiation that
gradually diminished over 7 days. Eye wipes, induced by hypertonic saline, were
quantified as a proxy for ocular surface pain. At 2 days following UVR
(300 mJ/cm2) exposure, exposed rats had a higher eye
wipe frequency (per 5 min) after the application of hypertonic saline (5 M) to the
cornea compared to control animals (~ 24 vs. ~ 13; p < 0.01), Concomitantly, at 2 days after exposure, hypertonic
saline also evoked significantly elevated neural response activity (measured by
total response magnitude [Rmag]) of superficial laminae in the
Vc/C1 region compared to controls (~ 900
spikes/stimulation vs. ~ 300 spikes/stimulation; p < 0.01). Interestingly, no change in activity was noted in the
Vi/Vc region [55]. These findings
suggest a role for Vc/C1 but not Vi/Vc in neural processing
of UVR and mechanistically explains the cutaneous hyperalgesia that often
accompanies UVR-induced damage [55,
56].
In another study, the Vi/Vc and Vc/C1
subnuclei of rats were each selectively activated using microinjections of
glutamate to determine which stimulation site would lead to tearing. In this
study, local stimulation of the Vi/Vc region, but not the
Vc/C1 region, resulted in significant increased tear
volume (milligram per 2 min) collected and measured 2 min after administration
(~ 1.7 vs. ~ 0.3; p < 0.001) [54]. Vi/Vc neurons may be grouped into type I
and type II units; type I units are defined by a monophasic dose-dependent
excitation response to carbon dioxide (CO2) pulses at the
ocular surface [75] while type II
units are defined by a biphasic response [75]. Type II units are thought to be moisture sensitive and to
have a role in detection of ocular surface dryness. In the same study, spontaneous
neural activity at the type II units of the Vi/Vc region was inhibited following
application of artificial tears at the ocular surface (> 75% decrease from
background; p < 0.01). Ten minutes after
artificial tear application, eyelid retraction and filter papers were used to dry
the ocular surface, resulting in a prompt increase in type II Vi/Vc unit
spontaneous activity to pre-wet levels. No changes were noted in the Vc/C1 region
in response to wetting or drying, pointing to the role of Vi/Vc in moisture
sensation and tear control [54].
These two studies reveal distinct functions of the Vc/C1
and Vi/Vc subnuclei in sensory processing.
Dysfunctional descending pain modulation may also play a role in
chronic ocular surface pain, as is also seen in other chronic pain syndromes
[59]. Descending inhibitory
activity is thought to originate from the thalamus and reticular system to
stimulate central gamma-aminobutyric acid (GABA) receptors, regulate interneurons,
and ultimately modify ascending pain signals at the level of the trigeminal
nucleus [76, 77]. In a study of male rats, the neural
activities of the Vi/Vc and Vc/C1 subnuclei were monitored
using microelectrodes following microinjections of muscimol, a
GABAA receptor-selective agonist. To test for
intersubnuclear communication, local muscimol microinjections were localized to
the rostral Vi/Vc transition region. In seven of the eight trials, spontaneous
neural activity at both the Vc/C1 and Vi/Vc subnuclei was
decreased by ≥ 50% with partial reversal following administration of bicuculline
methiodide, a GABAA antagonist [78]. These results suggest that
GABAA receptor mechanisms play a role in the modulation
of neural transmission at the level of second-order trigeminal neurons. These
animal studies provide valuable information about central pain processing at the
level of the trigeminal subnuclei.
Central Pain Processing and Functional Magnetic Resonance Imaging
Corneal pain sensation has been mapped out to its corresponding
location on the primary somatosensory cortex (S1) using functional magnetic
resonance imaging (fMRI) [71]. The
basis of fMRI is to detect local changes in oxygenation concentration (blood
oxygen level dependent [BOLD] contrast) related to increased neural activity
[79]. In a case study in
Massachusetts, neuroimaging using fMRI was performed on an individual with
photophobia due to a hard-contact lens-associated abrasion and compared to imaging
after recovery, 9 days later [80].
Bright light (6-s blocks, 65 lx) produced pain and blinking at the time of
abrasion and blinking alone after recovery. At the time of abrasion, several brain
areas were activated in response to light, including the contralateral middle of
the superior-inferior extent of S1 and bilateral primary motor cortices (M1) at
regions parallel to S1. After recovery, light activated the bilateral M1 regions
but not the S1 region [71]. Bright
light stimulation during the abrasion also produced specific activation patterns
in the ipsilateral trigeminal ganglion, bilateral trigeminal nucleus caudalis,
contralateral ventroposteromedial thalamus, anterior cingulate cortex, and middle
frontal gyrus. These areas were no longer activated with bright light after
recovery [80]. This study elegantly
localizes central areas involved in ocular surface pain processing in
humans.
Clinical Evaluation and Diagnosis
Similar to other eye pathologies, the diagnosis of ocular surface pain
requires a thorough history and clinical examination. Particular attention is paid to
chronicity, pain in relation to clinical signs, and subjective descriptors of pain such
as “burning” or “sensitivity to wind and light” in order to distinguish nociceptive and
neuropathic etiologies [4].
Nociceptive Pain at the Ocular Surface
The ocular surface pain evaluation begins by examining for sources of
nociceptive pain. These include abnormalities of the eyelids, conjunctiva, and tear
film. In the eyelids, particular attention should be paid to the presence of
ectropion, entropion, trichiasis [81,
82], lagophthalmos [83], laxity [84], and rosacea [85].
In the conjunctiva, the presence of conjunctivochalasis, pterygium, or superior
limbic keratoconjunctivitis must be evaluated [21, 86]. A tear film
exam should evaluate tear production and volume, which are reduced in aqueous tear
deficiency (ATD), and tear break-up time, which is reduced in both ATD and
evaporative DE. In addition, the presence of corneal and conjunctival staining should
be assessed with the appropriate vital dyes.
Neuropathic Pain at the Ocular Surface
Neuropathic ocular pain is a clinical diagnosis that can be made when
ocular surface pain persists after nociceptive sources of pain are diagnosed and
treated. There are no universal diagnostic criteria for neuropathic ocular pain
[2, 21]. However, some clues can be used to suggest the presence of a
neuropathic source to pain.
Symptoms Associated with NOP
First, certain pain descriptors, including symptoms of allodynia and
hyperalgesia, are more commonly seen in neuropathic versus nociceptive pain
[37]. The IASP defines allodynia as
“pain caused by a stimulus that does not normally provoke pain,” while hyperalgesia
is “increased pain from a stimulus that normally provokes pain” [3]. Based on these definitions, neuropathic
pain-specific questionnaires have been developed for the assessment of pain outside
the eye [87]. As briefly mentioned in
section Risk Factors and Associations, one such questionnaire is the Neuropathic Pain
Symptom Inventory (NPSI), which investigates for the presence and intensity of
different neuropathic pain symptoms (spontaneous ongoing pain, paroxysmal pain,
evoked pain, and paresthesias/dysesthesias) [87]. We modified the NPSI for use in the eye (NPSI-Eye), changing
evoked pain triggers to ones relevant for the eye; that is, cutaneous stimuli in the
original NPSI (i.e., brushing, pressure, and contact with cold) were revised to known
hyperalgesic/allodynic triggers in the eye (wind, light, and contact with something
hot or cold). In a study of 397 predominantly male Miami veterans with ocular surface
pain (NRS 0–10: ≥ 1 on average in the past week), correlations were found between
NPSI-Eye scores and general eye pain indicators, such as the NRS (ρ = 0.69, p < 0.001) and the short form McGill Pain Questionnaire (sf-MPQ)
(ρ = 0.65, p < 0.001). Furthermore, NPSI-Eye scores were significantly higher in
individuals suspected to have central ocular pain involvement (based on “no or
partial response” after placement of topical anesthesia to pain) compared to those
with “complete response” with anesthetic (40 ± 24 vs. 27 ± 21; p < 0.05). These data suggest preliminary validation
of the NPSI-Eye as a tool for the assessment of NOP [33].
The Ocular Pain Assessment Survey (OPAS) is another ocular pain
questionnaire that focuses on overall pain, not only on the neuropathic features of
pain [37]. OPAS assesses pain in the
past 24 h and past 2 weeks and includes numerical scales for pain intensity,
frequency, QoL impact, preoccupation with pain, aggravating and alleviating factors,
and associations. OPAS has questions on non-eye pain intensity, frequency, and
preoccupation. In a study of 102 individuals at the Massachusetts Eye and Ear
Infirmary, the OPAS was used to evaluate ocular pain in individuals with and without
eye pain of various etiologies, before and after treatment. Validity and internal
consistency of the OPAS were determined using the Wong-Baker FACES® Pain Rating Scale
(0–10 scale) as the gold standard method [88]. The OPAS was found to have criterion validity at both initial
(rs = 0.71, n = 102, p < 0.01)
and post-treatment follow-up visits (rs = 0.97, n = 21, p < 0.01), while 24-h
ocular pain scores from the OPAS were sensitive (94%), specific (81%), and accurate
(91%) [88]. These data suggest that pain
scales can be adapted to quantify ocular surface pain.
Diagnostic Tests Used in the Evaluation of NOP
Sensory testing can provide clues to whether ocular surface pain is
caused by nerve abnormalities. Corneal sensitivity can be examined qualitatively with
a cotton tip applicator or dental floss or quantitatively with Cochet–Bonnet and
Belmonte aesthesiometers. Both hypo- and hyperesthesia to stimuli can be seen in
individuals with NOP [37, 89].
Aesthesiometry
Simple tests for corneal sensation involve the applications of a
cotton swab, the tip of a tissue, or unwaxed dental floss to the ocular surface. A
numerical scale (NRS 0–3, referring to none, reduced, normal, and increased
sensation) may be used to characterize and monitor sensation over time
[90].
The Cochet–Bonnet aesthesiometer consists of a nylon monofilament
extending up to 6 cm in length that is first brought into contact with the ocular
surface and then retracted in 0.5-cm increments until corneal sensation is felt
[4]. In one Turkish study, 36
individuals with fibromyalgia but no known eye disease had higher corneal
sensitivity in the central, superior, and inferior quadrants compared to 39
controls (60.0 vs. 55.0 mm [p = 0.03] for
central cornea; 57.5 vs. 50.0 mm [p = 0.005]
for superior cornea; 53.9 vs. 46.0 mm [p < 0.001 ]for inferior cornea). OSDI scores were also higher in
the fibromyalgia group compared to controls (20 vs. 6; p < 0.001), with a positive correlation between OSDI and central
corneal sensitivity scores (r = 0.44, p = 0.007). However, no differences were found between
the groups in relation to tear parameters (Schirmer I test 16.1 vs. 15.3 mm; tear
film breakup time 17.8 vs. 18.8 s), and tear metrics did not relate to corneal
sensitivity [27]. This correlation
supports the association between corneal sensitivity and subjective reports of
ocular surface pain, even in the absence of ocular surface signs. Limitations of
the Cochet–Bonnet aesthesiometer include the need to touch the cornea and then
sterilize the filament, sensitivity measures can be impacted by room humidity and
temperature, sensitivity cannot be quantified past the fixed length of the
filament, and only a mechanical stimulus can be induced [91].
The Belmonte aesthesiometer utilizes a non-contact air jet to
provide the stimulus [4]. Mechanical
(variable air flow), thermal (hot or cold pulses), and chemical (varying
CO2 concentrations) stimuli can be administered to
determine corneal sensitivities in all three corneal nociceptors. In a French
study, 44 individuals with a prior diagnosis of DE were compared to 42 controls.
Individuals with a DE diagnosis reported various symptoms assessed on a scale of
0–4, including ‘burning or sandy sensation’ (mean 2.0 ± 1.1), ‘stinging’ (mean
1.9 ± 1.2), and ‘itching’ (mean 0.93 ± 1.2) while controls reported symptom scores
of ‘0′ for all three symptoms. Individuals with DE demonstrated significantly
higher mechanical (153 vs. 109 mL/min), chemical (23.9% CO2
vs. 16.4% CO2), heat (+ 0.34 °C vs. + 0.26 °C), and cold
(− 0.14 °C vs. − 0.05 °C) thresholds than controls using the Belmonte
aesthesiometer (all p < 0.001) [92], indicating decreased sensitivity to a
variety of stimuli. In contrast, a study of 129 Miami veterans with DE symptoms
found inverse correlations between pain (NRS score, NPSI-Eye total and subscales)
and corneal mechanical detection thresholds (log-transformed values) (r between − 0.15 and − 0.27) [93], indicating increased sensitivity to a
mechanical stimulus. Taken together, these studies demonstrate that both higher
and lower sensitivities can be seen in individuals with chronic ocular surface
pain. Limitations of the Belmonte aesthesiometer is that it is not commercially
available and thus requires in-house manufacturing, it is relatively large, and
threshold testing takes a significant amount of time. Thus, the device is better
adapted to the research, as opposed to the clinical, setting [4, 92].
Topical Anesthetics in Distinguishing Central and Peripheral NOP
Assessment of pain after the application of topical anesthetics is
another important test in the evaluation of nerve abnormalities [2, 45]. Given that ocular surface pain arises from pathologic
activation of central or peripheral origins, persistent pain after topical
anesthesia suggests that pain arises from a central or non-ocular surface source.
The rationale for this assumption is that because topical anesthetics dampen
peripheral inputs on the ocular surface, pain should be eliminated in individuals
with ocular surface damage or peripheral sensitization as a source of pain
[38]. In one study, 224
individuals with DE symptoms (Five-item Dry Eye Questionnaire [DEQ5] symptom
score ≥ 6) at the Miami Veterans Affairs Hospital were grouped by the presence of
persistent ocular pain 15 s following application of topical anesthesia
(proparacaine hydrochloride 0.5%). Compared to individuals with complete pain
resolution with anesthesia, those with persistent pain (n = 41) reported higher ocular pain intensity over the past week
(assessed using NRS 0–10: 5.3 ± 2.2 vs. 3.4 ± 2.3; p < 0.0005) and had higher NPSI-Eye scores (36 ± 22 vs. 23 ± 21;p < 0.0005). In addition, the group with
persistent pain reported higher intensities of hot-burning pain (4.9 ± 3.2 vs.
3.0 ± 2.9; p < 0.0005), sensitivity to light
(5.6 ± 3.1 vs. 3.2 ± 3.2; p < 0.005), and
sensitivity to wind (4.9 ± 3.6 vs. 2.9 ± 3.1; p = 0.02) [94]. These
results suggest that centrally mediated pain is associated with higher levels of
ocular pain intensity with a predilection for burning-type pain and evoked pain to
wind and light [45, 94]. A limitation of this test is that central
pain cannot be distinguished from non-ocular surface origins of pain.
Confocal Microscopy
In vivo confocal microscopy (IVCM) has been used to evaluate for the
presence of peripheral corneal nerve abnormalities. This technique allows
noninvasive in vivo imaging of corneal cellular architecture, nearly at the level
of histological visualization. The laser IVCM offers up to 800-fold magnification,
which can be used to examine and quantify cell characteristics and nerve density
immediately below the basal epithelium (subbasal nerve plexus), at a depth of
50–80 μm, and in the stroma [95]. In
a study in Nottingham (UK), 14 individuals (27 eyes) with severe, chronic
(> 1 year) and refractory ocular pain in the absence of ocular surface signs
were compared to seven healthy controls (14 eyes). Quantitative IVCM measures
included sub-basal nerve density (mm/mm2), epithelial
thickness (μm), presence of stromal microneuromas (spindle, lateral, and stump
neuromas), and grading of keratocyte activation (none, mild, moderate, and
severe). Keratocyte activation was defined as cellular changes (hyper-reflective
nuclei, visible cytoplasmic processes) and graded by location (anterior, mid, and
posterior stroma) and frequency. Individuals with ocular pain had significant
lower sub-basal nerve densities compared to controls (16.2 vs. 20.1; p < 0.008). In addition, all 27 eyes with ocular
pain had microneuromas in their stromal nerves (mean 4.59 per eye) which were not
seen in any controls. Finally, all eyes with ocular pain had keratocyte activation
(severe in 14.8%, moderate in 25.9%, and mild in 59.3%), which was not seen in
controls [45].
In the same study, the 27 eyes with ocular pain were grouped by
response to topical anesthesia (“no improvement of symptoms” [n = 20 eyes] vs. “marked improvement of symptoms”
[n = 7 eyes]). Individuals with no pain
after topical anesthesia had significantly higher numbers of stromal microneuromas
than those with persistent pain (9.3 vs. 3.0; p < 0.0001). Interestingly, no difference in central or peripheral
corneal sensation measured by Cochet–Bonnet aesthesiometry was found between the
two groups [45]. These data support
the paradigm that persistent pain after anesthesia suggests a central (or
non-ocular surface) source of pain while elimination of pain suggests peripheral
nerve abnormalities. The data also highlight that corneal sensitivity alone cannot
distinguish between peripheral and central sources of pain.
In a similar study at the Massachusetts Eye and Ear Infirmary, 16
individuals with symptoms of severe photophobia but no ocular surface
abnormalities were compared to 16 controls without photophobia. In this study,
however, IVCM was used to detect microneuromas in the sub-basal nerve plexus and
not the stroma, which were described as abrupt stump-like swellings of injured
nerve endings and neurite sprouting [96]. Sub-basal microneuromas were present in 62.5% of
individuals with ocular surface pain compared to 0% of controls [96]. These findings suggest that microneuromas
may be a marker of peripheral nerve abnormalities in individuals with ocular
surface pain. Limitations of confocal microscopy include the need for trained
operators to acquire high-quality scans, the need for contact between the
instrument and the eye, lack of age-adjusted nomograms for corneal nerve density,
and the lack of built-in software to quantify nerves and identify features such as
keratocyte activation and microneuromas. Furthermore, it is difficult to re-image
the exact location on follow-up and, coupled with the dynamic nature of nerves, it
is therefore difficult to monitor changes over time.
Approach to Treatment
Management of ocular surface pain depends on the underlying etiology. In
cases of nociceptive pain (i.e., trauma, anatomical abnormalities, tear film
instability, infection), treatment of the underlying condition will frequently lead to
prompt resolution of pain [21]. In
individuals with ongoing ocular surface inflammation and damage (e.g., Sjögren’s, GVHD),
topical anti-inflammatories, blood products, and contact lenses are often utilized to
help manage pain [2].
Recently, an intranasal electrical neurostimulation device, TrueTear
(Allergan, San Diego, CA, USA), was approved for increasing tear production in
individuals with DE. This handheld neurostimulation device uses two prongs applied at 45
degrees in the nostrils for 30–60 s of stimulation to activate the nasolacrimal reflex.
In a study of 75 individuals with DE symptoms (all DEQ5 ≥ 6; mean DEQ5 = 14.9), one
intranasal neurostimulation session using TrueTear increased tear volume (mean increase
of 13.4 ± 8.0 mm; p < 0.0005) and reduced ocular
pain (NRS 0–10: mean decrease of 1.48 ± 2.41; p < 0.0005) compared to baseline. Interestingly, changes in tear volume
and ocular pain were independent of one another (r = 0.07, p = 0.56), and those
individuals with low-moderate amounts of pain had the greatest amount of symptom
reduction [97]. This study demonstrates the
potential for intranasal stimulation to improve ocular pain symptoms in some individuals
with DE symptoms.
Treatment for neuropathic ocular pain should be considered when
nociceptive therapies fail and in individuals with appropriate symptoms, risk factors,
and clinical testing results. In cases of suspected peripheral neuropathic pain, local
therapies may be considered, including topical corticosteroids (i.e., loteprednol) or
nonsteroidal anti-inflammatory drugs (i.e., dicloflenac) [37], topical cyclosporine or lifitegrast [98], and autologous serum tears [96, 99].
Patients complaining of evaporation hypersensitivity may response therapeutically to
lubricants, goggles, soft and hard contact lenses, prosthetic replacement of the ocular
surface ecosystem (PROSE), or punctal occlusion [2].
Refractory peripheral symptoms and mixed and central neuropathic pain
merit systemic medical treatment. Gabapentin and pregabalin (α2γ ligands that modulate
central calcium channels) have been used in this regard at doses of 600 and 900 three
times daily and 150 twice daily, respectively, with renal dose adjustments in those with
creatine clearance < 60 mL/min [100,
101]. In a retrospective case study of
eight individuals with severe chronic ocular pain presumed to be due to neuropathic
mechanisms (i.e., persistent ocular pain after topical anesthetic, symptoms of
photophobia and burning, no adequate response to therapies targeting the ocular surface
and tears), gabapentin and pregabalin treatments were given starting at low doses
(300 mg daily for gabapentin and 25–75 mg daily for pregabalin) and escalated as needed.
Two individuals reported complete ocular pain relief on oral medication (NRS = 0 on a
0–10 scale), three reported significant pain improvements (NRS ≤ 2), one reported slight
but noticeable improvement (NRS = 10 at baseline, 7 at follow-up), and two reported no
improvement in pain [100]. This study
suggests that α2γ ligands may be applied to the treatment of chronic ocular surface
pain, as they have been successfully used for the treatment of many other types of
chronic pain syndromes [102]. Gabapentin
and pregabalin are frequently combined with other agents, including
serotonin-norepinephrine reuptake inhibitors, such as oral duloxetine 20–60 mg daily
[21].
Tricyclic antidepressants, such as nortriptyline (10–100 mg), have also
been used to treat individuals with chronic ocular surface pain, alone or in a
combination regimen with α2γ ligands [103]. In a retrospective study, 25 individuals clinically diagnosed with
refractory neuropathic corneal pain were treated with nortriptyline (10–100 mg) at Tufts
Medical Center. Mean follow-up pain scores (NRS 0–10) were lower 4 weeks post treatment
than at pretreatment (3.8 ± 2.4 vs. 6.4 ± 2.2; p < 0.0001), with pain improvement reported in 84% of patients (n = 21). Specifically, 28% reported > 50% improvement
(n = 7), 40% reported 25–50% improvement
(n = 10), and 32% reported < 25% improvement
(n = 8) [103]. Taken together, these studies suggest that medications used to
treat non-ocular pain can be applied to the treatment of ocular pain. In this regard,
there are other agents that are used to treat chronic pain that have not been
specifically tested but may also be beneficial in treating chronic ocular surface pain,
such as antiepileptics (i.e., topiramate, carbamazepine) and analgesics (i.e.,
mexiletine) [37, 104].
Adjuvant therapies that are used to treat non-ocular pain have also been
applied to the treatment of ocular surface pain. For example, transcutaneous electrical
nerve stimulation (TENS) delivers electrical stimuli at the level of the peripheral
nerves and has been used as an adjuvant treatment for multiple chronic pain conditions,
including facial pain [105, 106]. Our group investigated the use of the RS-4i
Plus Sequential Stimulator (RS-4i; RS Medical, Vancouver, WA, USA) in the treatment of
ocular pain by placing two pairs of electrodes above the brow and at the temple
bilaterally to generate an interferential current [105, 107]. In this
study, 14 individuals with chronic ocular pain (≥ 3 months) with a suspected neuropathic
component (i.e., discordance between significant ocular symptoms of burning or
photophobia and minimal ocular surface signs) were treated in an open-label fashion with
a one 30-min treatment. Mean pain intensity was significantly reduced 5 min post
treatment as compared to pretreatment (0–10 NRS: right eye 4.5 ± 3.2 to 1.9 ± 2.5
[p = 0.01]; left eye 4.5 ± 3.4 to 2.0 ± 2.4
[p = 0.01]) [105]. The feasibility of using TENS for the long-term treatment of
ocular surface pain was investigated in another study of ten individuals followed for a
mean of 6.6 ± 3.6 months. All ten individuals were able to incorporate the TENS unit
into their ocular pain treatment for at least 3 months (with all reporting continued
TENS use at last point of contact) and, overall, ocular pain scores decreased with the
use of TENS compared to baseline (5.6 vs. 7.6; p = 0.02) [108]. The results
of this study substantiate the positive effect of including non-pharmacologic adjuvants
in the long-term management of refractory chronic ocular surface pain.
Botulinum toxin type A (BoNT-A) has also been investigated as an adjuvant
treatment for ocular surface pain [109].
CGRP is a known inflammatory neuropeptide found on the ocular surface [20], and BoNT-A is thought to interfere with the
release of CGRP and other similar mediators [109]. In a study of 62 individuals with chronic migraine treated with
BoNT-A (100–150 units every 3 months based on migraine protocol), BoNT-A not only
decreased migraine pain 4–6 weeks post treatment compared to pretreatment but also
interictal photophobia (3.4 ± 2.5 vs. 4.9 ± 3.0; p < 0.001) and overall light sensitivity (assessed using the Visual Light
Symptom Questionnaire [VLSQ]-8 [110]:
27.7 ± 6.5 vs. 29.8 ± 5.1; p = 0.002). Responses to
the questions in the VLSQ-8 questionnaire revealed improvements in frequency of glare
(2.9 ± 1.3 vs. 3.4 ± 0.86; p = 0.001), light
sensitivity from flickering lights or bright colors (3.1 ± 1.3 vs. 3.7 ± 1.0; p = 0.004), and severity of worst period of photophobia
(3.7 ± 1.0 vs. 4.2 ± 0.88; p = 0.001) in the past
month [111]. Interestingly, these findings
were independent of tear volume, again suggesting that ocular surface findings do not
drive ocular surface pain in many individuals. In this regard, other agents that block
CGRP, such as erenumab, eptinezumab, galcanezumab, fremanezumab, may also have a
beneficial effect on chronic ocular pain [112, 113]. However, this
strategy remains to be tested.
Periocular nerve blockade (supraorbital, supratrochlear, infraorbital,
infratrochlear nerve pathways) [100] is
another invasive treatment option that has been used to treat chronic ocular pain. In
one study, a corticosteroid/anesthetic combination (i.e., 4 mL 0.5% bupivacaine mixed
with 1 mL 80 mg/mL methylprednisolone acetate) was injected around one or more
periocular nerves in 11 individuals with chronic ocular surface pain. Improvement of
pain was noted in seven individuals, with no change reported in the remaining four.
These improvements were variable, lasting from hours to months [100]. In addition to other case reports
[21, 100, 114], this study
supports the use of periocular nerve blocks in the management of refractory ocular
surface pain.
More invasive measures may be required in the treatment of refractive
pain, including blockade of sphenopalatine and superior cervical ganglions and
implantation of long-term devices. For example, one case demonstrated improvement in
refractory ocular surface pain following the implantation of a stimulating trigeminal
ganglion electrode and high cervical intrathecal pain pump (consisting of bupivacaine
and low-dose fentanyl) [115]. This report
highlights the morbidity and suffering caused by ocular surface pain, in that an
individual was willing undergo such invasive measures to attempt pain relief.
Acupuncture has been investigated as an adjunctive treatment for ocular
surface pain. In a prospective study in Pittsburgh (PA), individuals with DE (based on
prior DE diagnosis and a score of ≥ 1 on an 0–4 NRS for any ocular symptom [e.g.,
discomfort, dryness, scratchiness, burning] that persisted > 1 month) were grouped
into acupuncture (n = 24) and sham groups (n = 25). The acupuncture protocol consisted of 12 needles in
total (i.e., 6 on the bilateral ears, 6 on the bilateral index fingers) left in place
for 45 min. The sham treatment consisted of eight needles in total (on the bilateral
upper shoulders outside of known acupuncture points). The active treatment group
(baseline OSDI 34 ± 17) demonstrated significant improvements in symptoms at 1 week
(19 ± 17; p < 0.01), 1 month (21 ± 17; p < 0.05), 3 months (20 ± 21; p < 0.05), and 6 months (16 ± 12; p < 0.01). Improvements were also noted in the sham group, although to a
smaller degree, from a baseline OSDI of 36 ± 20 to lower scores at 1 week (24 ± 22), 1
month (24 ± 21), 3 months (21 ± 20), and 6 months (25 ± 18) [116]. Further data regarding the efficacy of
acupuncture in the treatment of ocular surface pain areneeded, given its use in treating
other neuropathic pain conditions [37,
117].
Given the close association of chronic ocular surface pain with
psychological discomfort, poor coping mechanisms [11], mood disorders, and QoL factors, cognitive–behavioral therapy
(CBT) should be considered in individuals suffering from chronic pain [4, 118].
While no data have evaluated the efficacy of CBT in chronic ocular surface pain, studies
have demonstrated CBT to be a viable treatment adjuvant in non-ocular pain conditions
[102, 119]. In a multicenter randomized controlled trial in England, 598
adults with subacute or chronic low-back pain were separated into a randomly selected
CBT-intervention group (n = 399) and control group
(n = 199), with both groups receiving advice for
low-back pain management. At the 12-month analysis, the modified Von Korff pain scale
(range 0–100%) was used to show significant improvements in back pain in the CBT plus
advice group compared to the control group (mean pain scale decrease by 13.8 vs. 5.4%;p < 0.0001) [119]. Another study pooled four RCTs of CBT in fibromyalgia patients
in a meta-analysis. CBT in fibromyalgia patients as compared to usual care or a waitlist
resulted in small improvements in pain (range 0–10 NRS) within 6 months of follow-up
(pooled difference − 0.62, 95% confidence interval − 1.08 to − 0.14) [102]. These studies support the use of CBT as an
adjuvant treatment in individuals with chronic ocular surface pain.
Conclusion
Chronic ocular surface pain can arise from a number of abnormalities
including ongoing tissue injury as well as peripheral and central neurologic mechanisms.
A first step in approaching patients is a comprehensive evaluation looking for sources
of pain. In individuals with a suspected neuropathic component to pain, an
interdisciplinary approach is critical, considering psychological, behavioral, and
neurologic contributors. Easing the burden of chronic ocular pain requires further
exploration of its neurophysiology, diagnostic modalities, and treatment
strategies.
Acknowledgements
Funding
This research was supported by the Department of Veterans Affairs,
Veterans Health Administration, Office of Research and Development, Clinical Sciences
Research I01 CX002015 (A. Galor), Biomedical Laboratory R&D (BLRD) Service I01
BX004893 (A. Galor), Department of Defense GW190010 (A. Galor), R01EY026174 (A.
Galor), NIH Center Core Grant P30EY014801 and Research to Prevent Blindness
Unrestricted Grant. No funding or sponsorship was received for the publication of
this article.
Authorship
All named authors meet the International Committee of Medical Journal
Editors (ICMJE) criteria for authorship for this article, take responsibility for the
integrity of the work as a whole, and have given their approval for this version to
be published.
Disclosures
Divy Mehra, Noah K Cohen, and Anat Galor declare that they have no
conflict of interest.
Compliance with Ethics Guidelines
This article is based on previously conducted studies and does not
contain any studies with human participants or animals performed by any of the
authors.
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