Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04454281 |
| Other study ID # |
48303 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 1
|
| First received |
|
| Last updated |
|
| Start date |
October 1, 2020 |
| Est. completion date |
December 3, 2020 |
Study information
| Verified date |
November 2022 |
| Source |
University of Kentucky |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Chronic ocular neuropathic pain may be misdiagnosed as dry eye disease. Our study aims to
identify a population with previous monocular trauma and dry eye symptoms and differentiate
neuropathic from dry eye pain using topical corneal naloxone hydrochloride.
Description:
Dry eye is a ubiquitous and debilitating ocular condition that affects tens of millions in
the United States (DEWS, 2007). However, there is increasing evidence that the symptoms of
dry eye overlap with the distinct condition of ocular neuropathic pain, and that many
patients given a dry eye diagnosis are mislabeled (Galor, 2017). These shared symptoms
include but are not limited to: hypoesthesia, hyperalgesia, and allodynia. According to the
2017 DEWS II (Dry Eye Workshop) pain and sensation report by the Tear Film and Ocular Surface
Society, neuropathic pain can manifest itself in the eye and may present similarly to dry
eye, but should not be classified as such (Belmonte, 2017). Our study aims to further
characterize this distinction by translating the rodent model of latent sensitization to the
human eye.
Latent sensitization is a model of chronic pain that reproduces both its episodic nature and
its sensitivity to stress. It can be induced by an array of insults and follows a
characteristic time course in which a hyperalgesic pain phase is followed by pain remission
phase. Of clinical relevance, administration of mu-opioid antagonists (i.e. naloxone) during
the remission phase reinstates animal pain behavior and physiologic reflexes to peak levels
seen in the hyperalgesia phase (Marvizon, 2015). This phenomenon suggests that the animals
are in a state of latent sensitization that can be unmasked by blocking the activity of the
opioid signaling pathway through compounds like naloxone hydrochloride. Furthermore, the
undulating course of chronic pain syndromes can be mimicked by introducing environmental and
physical stressors that trigger and exacerbate pain states (Marvizon, 2015).
Neuropathic pain is a common cause of chronic pain. It is defined by the International
Association for the Study of Pain as pain that arises as a direct consequence of a lesion or
disease affecting the somatosensory system. In contrast, nociceptive pain is produced by the
normal function of nociceptors. Hence, neuropathic lesions do not necessarily involve the
nociceptive pathway; instead, they can involve other somatosensory pathways including
tactile, mechanical, and thermal pathways. These lesions manifest allodynia-a central pain
sensation following a normally non-painful stimuli and a clinical hallmark of neuropathic
pain. In the eye, allodynia may manifest as non-specific dry-eye-like-symptoms to stimuli
including wind, temperature change, and humidity (Galor, 2017).
Hyperalgesia is a heightened pain sensation to a normally painful stimulus and is another
hallmark of neuropathic pain. Importantly, hyperalgesia is a symptom of both neuropathic and
nociceptive pain, however the pathophysiologies are distinct. Neuropathic hyperalgesia is a
sustained phenomenon that arises from neuronal remodeling and sensitization of nociceptive
peripheral and/or central nerves. In distinction, nociceptive hyperalgesia arises from
inflammatory cytokine mediators that sensitize nociceptors and resolves after the conclusion
of inflammation. Given all of this, it can be difficult to clinically differentiate the two
forms of hyperalgesia; similarly, it can be difficult to differentiate between neuropathic
and nociceptive pain.
In our murine model (Cho, 2019), we study latent sensitization of the eye after injuring the
cornea with an alkali solution. We find that pain behavior (quantified by the number of eye
wipes in thirty seconds after the topical administration of 2M NaCl to the corneal surface)
peaks at day 10 post injury and returns to baseline by day 14 post injury (figure 3.1; next
page). Topical administration of naloxone (100uM, one drop), reinstated peak pain behavior 16
weeks after initial corneal surface injury (figure 3.2; next page).
We hypothesize that our patient population with monocular trauma and dry eye symptoms mirrors
our murine model. The monocular trauma represents the initial corneal surface injury, and the
dry eye symptoms represent the breakthrough pain. It is important to note that in other
models of latent sensitization, peak pain responses can be reinstated by stressors other than
opioid antagonism. Specifically, novel environment stressors and forced swims reproduce peak
pain behavior experienced in the hyperalgesic phase. In a similar way, our patient population
endorses exacerbation of dry eye symptoms in the setting of stress, sleep, and environmental
changes.
Our study aims to differentiate dry eye disease from ocular neuropathic pain by testing the
latent sensitization model in the human eye. Given that there is good data to suggest chronic
pain states, including our ocular model, can be masked by upregulation of the mu-opioid
receptor signaling pathway, we hypothesize that our naloxone hydrochloride drop will induce a
hyperalgesic response to hypertonic saline in a population with dry eye diagnosis and
monocular trauma. We believe a topical naloxone ophthalmic drop is a potentially easy, cheap,
and safe diagnostic tool for ocular neuropathic pain.
