<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04454281</url>
  </required_header>
  <id_info>
    <org_study_id>48303</org_study_id>
    <nct_id>NCT04454281</nct_id>
  </id_info>
  <brief_title>Topical Naloxone to Diagnose Ocular Pain</brief_title>
  <official_title>Topical Naloxone Hydrochloride as a Diagnostic Tool for Ocular Neuropathic Pain</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Seema Capoor</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Kentucky</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Chronic ocular neuropathic pain may be misdiagnosed as dry eye disease. Our study aims to&#xD;
      identify a population with previous monocular trauma and dry eye symptoms and differentiate&#xD;
      neuropathic from dry eye pain using topical corneal naloxone hydrochloride.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Dry eye is a ubiquitous and debilitating ocular condition that affects tens of millions in&#xD;
      the United States (DEWS, 2007). However, there is increasing evidence that the symptoms of&#xD;
      dry eye overlap with the distinct condition of ocular neuropathic pain, and that many&#xD;
      patients given a dry eye diagnosis are mislabeled (Galor, 2017). These shared symptoms&#xD;
      include but are not limited to: hypoesthesia, hyperalgesia, and allodynia. According to the&#xD;
      2017 DEWS II (Dry Eye Workshop) pain and sensation report by the Tear Film and Ocular Surface&#xD;
      Society, neuropathic pain can manifest itself in the eye and may present similarly to dry&#xD;
      eye, but should not be classified as such (Belmonte, 2017). Our study aims to further&#xD;
      characterize this distinction by translating the rodent model of latent sensitization to the&#xD;
      human eye.&#xD;
&#xD;
      Latent sensitization is a model of chronic pain that reproduces both its episodic nature and&#xD;
      its sensitivity to stress. It can be induced by an array of insults and follows a&#xD;
      characteristic time course in which a hyperalgesic pain phase is followed by pain remission&#xD;
      phase. Of clinical relevance, administration of mu-opioid antagonists (i.e. naloxone) during&#xD;
      the remission phase reinstates animal pain behavior and physiologic reflexes to peak levels&#xD;
      seen in the hyperalgesia phase (Marvizon, 2015). This phenomenon suggests that the animals&#xD;
      are in a state of latent sensitization that can be unmasked by blocking the activity of the&#xD;
      opioid signaling pathway through compounds like naloxone hydrochloride. Furthermore, the&#xD;
      undulating course of chronic pain syndromes can be mimicked by introducing environmental and&#xD;
      physical stressors that trigger and exacerbate pain states (Marvizon, 2015).&#xD;
&#xD;
      Neuropathic pain is a common cause of chronic pain. It is defined by the International&#xD;
      Association for the Study of Pain as pain that arises as a direct consequence of a lesion or&#xD;
      disease affecting the somatosensory system. In contrast, nociceptive pain is produced by the&#xD;
      normal function of nociceptors. Hence, neuropathic lesions do not necessarily involve the&#xD;
      nociceptive pathway; instead, they can involve other somatosensory pathways including&#xD;
      tactile, mechanical, and thermal pathways. These lesions manifest allodynia-a central pain&#xD;
      sensation following a normally non-painful stimuli and a clinical hallmark of neuropathic&#xD;
      pain. In the eye, allodynia may manifest as non-specific dry-eye-like-symptoms to stimuli&#xD;
      including wind, temperature change, and humidity (Galor, 2017).&#xD;
&#xD;
      Hyperalgesia is a heightened pain sensation to a normally painful stimulus and is another&#xD;
      hallmark of neuropathic pain. Importantly, hyperalgesia is a symptom of both neuropathic and&#xD;
      nociceptive pain, however the pathophysiologies are distinct. Neuropathic hyperalgesia is a&#xD;
      sustained phenomenon that arises from neuronal remodeling and sensitization of nociceptive&#xD;
      peripheral and/or central nerves. In distinction, nociceptive hyperalgesia arises from&#xD;
      inflammatory cytokine mediators that sensitize nociceptors and resolves after the conclusion&#xD;
      of inflammation. Given all of this, it can be difficult to clinically differentiate the two&#xD;
      forms of hyperalgesia; similarly, it can be difficult to differentiate between neuropathic&#xD;
      and nociceptive pain.&#xD;
&#xD;
      In our murine model (Cho, 2019), we study latent sensitization of the eye after injuring the&#xD;
      cornea with an alkali solution. We find that pain behavior (quantified by the number of eye&#xD;
      wipes in thirty seconds after the topical administration of 2M NaCl to the corneal surface)&#xD;
      peaks at day 10 post injury and returns to baseline by day 14 post injury (figure 3.1; next&#xD;
      page). Topical administration of naloxone (100uM, one drop), reinstated peak pain behavior 16&#xD;
      weeks after initial corneal surface injury (figure 3.2; next page).&#xD;
&#xD;
      We hypothesize that our patient population with monocular trauma and dry eye symptoms mirrors&#xD;
      our murine model. The monocular trauma represents the initial corneal surface injury, and the&#xD;
      dry eye symptoms represent the breakthrough pain. It is important to note that in other&#xD;
      models of latent sensitization, peak pain responses can be reinstated by stressors other than&#xD;
      opioid antagonism. Specifically, novel environment stressors and forced swims reproduce peak&#xD;
      pain behavior experienced in the hyperalgesic phase. In a similar way, our patient population&#xD;
      endorses exacerbation of dry eye symptoms in the setting of stress, sleep, and environmental&#xD;
      changes.&#xD;
&#xD;
      Our study aims to differentiate dry eye disease from ocular neuropathic pain by testing the&#xD;
      latent sensitization model in the human eye. Given that there is good data to suggest chronic&#xD;
      pain states, including our ocular model, can be masked by upregulation of the mu-opioid&#xD;
      receptor signaling pathway, we hypothesize that our naloxone hydrochloride drop will induce a&#xD;
      hyperalgesic response to hypertonic saline in a population with dry eye diagnosis and&#xD;
      monocular trauma. We believe a topical naloxone ophthalmic drop is a potentially easy, cheap,&#xD;
      and safe diagnostic tool for ocular neuropathic pain.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 1, 2020</start_date>
  <completion_date type="Actual">December 3, 2020</completion_date>
  <primary_completion_date type="Actual">December 3, 2020</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Pain Response to Hypertonic Saline (Muro 128) drop</measure>
    <time_frame>Immediately after hypertonic drop administered. Measured during both study visits, thus through study completion, an expected average of 4 weeks.</time_frame>
    <description>The pain response is graded using a Visual Analog Scale (VAS) survey. It is graded 1-10; 10 indicates the most severe pain.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Ocular Surface Disease Index</measure>
    <time_frame>At any point during study visit. Measured during both study visits, thus through study completion, an expected average of 4 weeks.</time_frame>
    <description>This 12 question survey measures your recent dry eye symptoms using the ocular surface index scale. The scale has a low score of 10 and high score of 100. A higher score means you have worse dry eye symptoms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Slit Lamp Biomicroscopy</measure>
    <time_frame>Before and after hypertonic saline drop. Measured during both study visits, thus through study completion, an expected average of 4 weeks.</time_frame>
    <description>This test examines many areas of your eye (cornea, lids, inner eye) using a microscope.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Flourescein corneal examination</measure>
    <time_frame>Before and after hypertonic saline drop. Measured during both study visits, thus through study completion, an expected average of 4 weeks.</time_frame>
    <description>A yellow staining dye will be applied to your cornea that will allow us to examine the structural integrity of your cornea.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>intraocular pressure</measure>
    <time_frame>Before and after hypertonic saline drop. Measured during both study visits, thus through study completion, an expected average of 4 weeks.</time_frame>
    <description>Intraocular pressure will be measured via Tono-Pen.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>visual acuity</measure>
    <time_frame>Before and after hypertonic saline drop. Measured during both study visits, thus through study completion, an expected average of 4 weeks.</time_frame>
    <description>will be measured using ETDRS letter grading system. Your grade will depend on your ability to read small print.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">1</enrollment>
  <condition>Dry Eye Syndromes</condition>
  <condition>Neuropathic Pain</condition>
  <arm_group>
    <arm_group_label>Naloxone HCl Low dose: 0.02 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This arm will receive 0.02 mg naloxone hcl on the experimental visit and balance salt solution on the control visit.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Naloxone HCl High dose: 0.08 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This arm will receive 0.08 mg naloxone hcl on the experimental visit and balance salt solution on the control visit.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Naloxone Hydrochloride 0.4 MG/ML</intervention_name>
    <description>Drug will be topically applied to the corneal surface then study evaluations will ensue.</description>
    <arm_group_label>Naloxone HCl High dose: 0.08 mg</arm_group_label>
    <arm_group_label>Naloxone HCl Low dose: 0.02 mg</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  monocular trauma&#xD;
&#xD;
          -  dry eye disease diagnosis&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  any pathology that might contribute to ocular pain, including corneal surface ulcers,&#xD;
             uveitis, or other chronic inflammatory processes&#xD;
&#xD;
          -  any current corneal surface pathology&#xD;
&#xD;
          -  history of bilateral ocular trauma&#xD;
&#xD;
          -  currently taking any of the following medications: TCAs, opioids, gabapentin, SNRIs&#xD;
&#xD;
          -  pregnant nor breastfeeding.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Seema Capoor, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Kentucky</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Kentucky</name>
      <address>
        <city>Lexington</city>
        <state>Kentucky</state>
        <zip>40506</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>June 24, 2020</study_first_submitted>
  <study_first_submitted_qc>June 26, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 1, 2020</study_first_posted>
  <last_update_submitted>November 4, 2022</last_update_submitted>
  <last_update_submitted_qc>November 4, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 8, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Kentucky</investigator_affiliation>
    <investigator_full_name>Seema Capoor</investigator_full_name>
    <investigator_title>Principal Investigator, Assistant Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neuralgia</mesh_term>
    <mesh_term>Dry Eye Syndromes</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Naloxone</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04454281
org study id: 48303
nct id: NCT04454281
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
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.
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.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Diagnostic
masking: Triple (Participant, Care Provider, Investigator)
measure: Pain Response to Hypertonic Saline (Muro 128) drop
time frame: Immediately after hypertonic drop administered. Measured during both study visits, thus through study completion, an expected average of 4 weeks.
description: The pain response is graded using a Visual Analog Scale (VAS) survey. It is graded 1-10; 10 indicates the most severe pain.
measure: Ocular Surface Disease Index
time frame: At any point during study visit. Measured during both study visits, thus through study completion, an expected average of 4 weeks.
description: This 12 question survey measures your recent dry eye symptoms using the ocular surface index scale. The scale has a low score of 10 and high score of 100. A higher score means you have worse dry eye symptoms.
measure: Slit Lamp Biomicroscopy
time frame: Before and after hypertonic saline drop. Measured during both study visits, thus through study completion, an expected average of 4 weeks.
description: This test examines many areas of your eye (cornea, lids, inner eye) using a microscope.
measure: Flourescein corneal examination
time frame: Before and after hypertonic saline drop. Measured during both study visits, thus through study completion, an expected average of 4 weeks.
description: A yellow staining dye will be applied to your cornea that will allow us to examine the structural integrity of your cornea.
measure: intraocular pressure
time frame: Before and after hypertonic saline drop. Measured during both study visits, thus through study completion, an expected average of 4 weeks.
description: Intraocular pressure will be measured via Tono-Pen.
measure: visual acuity
time frame: Before and after hypertonic saline drop. Measured during both study visits, thus through study completion, an expected average of 4 weeks.
description: will be measured using ETDRS letter grading system. Your grade will depend on your ability to read small print.
arm group label: Naloxone HCl Low dose: 0.02 mg
arm group type: Experimental
description: This arm will receive 0.02 mg naloxone hcl on the experimental visit and balance salt solution on the control visit.
arm group label: Naloxone HCl High dose: 0.08 mg
arm group type: Experimental
description: This arm will receive 0.08 mg naloxone hcl on the experimental visit and balance salt solution on the control visit.
intervention type: Drug
intervention name: Naloxone Hydrochloride 0.4 MG/ML
description: Drug will be topically applied to the corneal surface then study evaluations will ensue.
arm group label: Naloxone HCl High dose: 0.08 mg
arm group label: Naloxone HCl Low dose: 0.02 mg
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Seema Capoor, MD
role: Principal Investigator
affiliation: University of Kentucky
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: University of Kentucky
investigator full name: Seema Capoor
investigator title: Principal Investigator, Assistant Professor
mesh term: Neuralgia
mesh term: Dry Eye Syndromes
mesh term: Naloxone
sharing ipd: No