Diode Laser as a Biomarker for Neuropathic Pain of Peripheral Origin. (DLss)

April 15, 2026 updated by: Rob Singleton, University of Utah
The R61 will perform a four-part double-blind randomized crossover study transitioning from a pretreatment baseline phase, to randomized treatment with either lidocaine or an identical placebo patch, washout, and alternate arm. DLss measures will be obtained before and after each phase. Twice daily report of pain using a visual analogue scale will track severity of ongoing spontaneous pain in participants. The hybrid biomarker will distinguish between placebo and active treatment arms, will significantly correlate with extent of neuropathic pain reduction during lidocaine, but will not change during the placebo phase or no-treatment lead-in. If preset Go/No-Go criteria are met, the subsequent R33 validation will then compare lidocaine patch and placebo treatment in a blinded, randomized parallel arm study.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Pain caused by peripheral neuropathy is very common. Understanding patient response to pain and its treatment is one of the biggest barriers to development of effective medicines to reduce neuropathic pain. This project will develop and validate a non-invasive test that correlates with patients' experience of pain caused by peripheral neuropathy, a "pain biomarker". The biomarker device applies specialized light energy to skin on the top of the foot to selectively stimulate the nerve fibers in skin that sense and transmit pain. The test will determine how much energy is necessary to cause a person to feel the stimulus, or to first feel the pain of the stimulus. Sensory threshold to the stimulus, and transient enhancement of blood flow in the skin (flare) will be correlated with patient report of ongoing foot pain. Use of the experimental device, diagnostic testing, and use of lidocaine have risks that are explained in this document, but can include allergic reactions, discomfort, and temporary numbness.

SUMMARY OF STUDY PROCEDURES This study is being conducted by Drs. J. Robinson Singleton in the Department of Neurology at the University of Utah, and by Mikhail Nemenov PhD, of Stanford University, who developed the use of this technique for stimulating nerves in the skin. Study 1 will correlate the biomarker with patients' reported ongoing neuropathic foot. You may also be asked to participate in the Study 2, in which change in the biomarker will be correlated longitudinally to change in pain experience in a brief, randomized crossover trial of placebo or lidocaine patches applied to the top of the foot.

Optimization of DLss Biomarker in Healthy Subjects (Stanford and Utah)

Healthy subjects will be screened to exclude neuropathy, foot pain and diabetes then will have the DLss measures performed over several days. The visit lasts about 3-4 hours.

Study 1: biomarker correlation with ongoing pain (Utah)

This study consists of a single visit designed to evaluate possible neuropathy and assess its severity with history, standardized brief exam, and specialized testing. All participants will then rate their ongoing foot pain, and biomarker testing will be performed. The entire visit will take 2-3 hours. The purpose is to correlate the biomarker with patients reported ongoing neuropathic foot pain.

People with peripheral neuropathy. A total of 50 people will participate.

Study 2: biomarker correlation with change in pain during lidocaine treatment (Utah)

Study 2 is designed to see if change in neuropathic pain from treatment with an effective pain reducing agent correlates with change in the biomarker. Lidocaine, a locally acting anesthetic, will be applied to the top of the foot using a patch. The study is structured as a 4 week blinded and randomized crossover treatment trial and will five consist of 5 brief weekly study visits, once weekly over the 4 week study period. Crossover means that you will receive both treatments for a week each. Randomized means that the treatment you receive first, placebo or Lidocaine patch, will be chosen at random. Blinded means that you will not be told whether the treatment you receive during the treatment weeks is placebo or Lidocaine. The patches will look similar or identical. Neither you, nor the study coordinator will be able to tell the identity of the patches.

Study Segments: Each weekly segment of the study is proceeded and followed by a visit, in sequence. Each visit will include review of neuropathic pain and performance of QST and Biomarker Device assessment. There are four segments:

  1. Baseline neuropathic pain evaluation. Each participant will be screened in clinic, then record daily pain severity for 7 days.
  2. Treatment period 1. After this baseline period, each participant will be randomized to 7 days of treatment with a patch (either lidocaine or placebo) chosen by the study at random.
  3. A 7-day wash out period without treatment.
  4. Treatment period 2. Daily treatment with patch not received in the first treatment period.

A total of 44 people with neuropathy and associated neuropathic pain will participate

Study Type

Interventional

Enrollment (Actual)

75

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Palo Alto, California, United States, 94305
        • Stanford University
    • Utah
      • Salt Lake City, Utah, United States, 84132
        • University of Utah

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

Inclusion criteria for Objective 1 (Healthy Controls)

  1. 18-70 years of age
  2. no complaints of peripheral neuropathy or other foot pain
  3. no medical history of disease or medication use associated with peripheral neuropathy (e.g. diabetes)
  4. DLss 3-questions and sharp sensation testing indicate neuropathy is not present.

4a Do you have persistent numbness or tingling in your feet? 4b Do you have pain in your feet that is not due to an orthopedic injury or lesions to skin/toenails? 4c Do you have problems with your balance? 5) no known allergy to lidocaine

Inclusion Criteria for Objective 2 - Neuropathy Correlation

  1. . 18 years of age and older
  2. Length dependent, sensory predominant, peripheral neuropathy from any non-acute acquired cause (e.g. diabetes, pre-diabetes, chemotherapy induced), OR musculoskeletal pain from plantar fasciitis or ankle sprain.

Inclusion Criteria for Cross Over

  1. 18 years old or older:
  2. Pain rating on Average Visual Analog Scale (VAS) > 30mm or Worst Visual Analog Scale (VAS) > 40mm
  3. UENS score greater than or equal to 4 or a length dependent, sensory predominant, peripheral neuropathy from any non-acute acquired cause based on the opinion of the investigator:

Exclusion Criteria:

  1. Current peripheral neuropathy that is rapidly changing (e.g. Guillain Barre syndrome or glucose correction neuropathy) :
  2. Severe liver disease (ie: untreated/active hepatitis) :
  3. Currently receiving chemotherapy:
  4. Recent or planned change in neuropathic pain medication during study (approximately 7 weeks) :
  5. Structural defects in foot that result in participant being unable to differentiate between neuropathic pain and another source of pain (ie: plantar fasciitis, arthritis) :
  6. Unable to comply with protocol requirements or is at undue risk as judged by the investigator :

Exclusion Criteria for Patch Cross Over

  1. Known allergy to topical lidocaine or other patch ingredients (ie adhesive, butylated hydroxytoluene, dipropylene glycol, silicon dioxide, styrene/isoprene/sytrene copolymer):
  2. Use of topical lidocaine patch or other topical neuropathic pain creams on feet (e.g. capsaicin) :
  3. Taking medications similar to lidocaine or with anti-arrhythmic properties (ie: tocainide or mexiletine) :
  4. Known allergy to lidocaine or other para-aminobenzoic acid derivative (e.g. procaine, tetracaine, benzocaine) :

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Sequential Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Biomarker Optimization (Stanford)
Screening for neuropathy, foot problems and diabetes Diode laser testing of C:Aδ ratio Non-invasive speckle imaging Quantitative sensory testing ZTlido 1.8% lidocaine patch testing in some subjects
Procedure: Diode Laser fiber type Selective Stimulator
-Each patient will have an A and C fiber stimulation. Stimulation will be performed on the dorsum of the foot using stimulation previously published parameters to elicit "burning pain," which is from activation of C-fibers and "pinprick" pain from A-fib
Other Names:
  • DLss
Diagnostic test: PeriCam PSI NR
It is a method that visualizes tissue blood perfusion in real time. LASCA provides new means to study the microcirculation in ways that were not possible in the past. PeriCam PSI System combines dynamic response and high spatial resolution in one instrument, providing both real-time graphs and video recordings of the tissue being studied. To further enhance its usability, dedicated application software, PIMSoft, has been developed.
Other Names:
  • speckle imager
Diagnostic test: Medoc Quantitative Sensory Testing

Quantitative sensory testing (QST) is a method through which sensory nerve function is quantitatively measured, based on responses of the subject. The peripheral sensory nervous system responds to specific stimuli of specific modality and intensity in a specific manner, which is well-known through many decades of research into human sensation. Thermal QST provides information about the function of small diameter unmyelinated (C fibers) and thinly myelinated (A-delta fibers) nerve fibers for which no nerve conduction test, or other objective tests exist.

Small fiber nerve damage can manifest itself in thermal hypoesthesia (raised perception thresholds) or hyperalgesia (lowered pain thresholds).

Other Names:
  • QST
Experimental: Neuropathy assessment and biomarker testing (Utah)
History, physical, and neurological exam Nerve conduction study Medical record review of neuropathy history PROMIS pain severity and interference testing Brief pain inventory Norfolk quality of life questionnaire Quantitative sensory testing 3mm skin punch biopsy Diode laser testing of C:Aδ ratio Non-invasive speckle imaging
Procedure: Diode Laser fiber type Selective Stimulator
-Each patient will have an A and C fiber stimulation. Stimulation will be performed on the dorsum of the foot using stimulation previously published parameters to elicit "burning pain," which is from activation of C-fibers and "pinprick" pain from A-fib
Other Names:
  • DLss
Diagnostic test: PeriCam PSI NR
It is a method that visualizes tissue blood perfusion in real time. LASCA provides new means to study the microcirculation in ways that were not possible in the past. PeriCam PSI System combines dynamic response and high spatial resolution in one instrument, providing both real-time graphs and video recordings of the tissue being studied. To further enhance its usability, dedicated application software, PIMSoft, has been developed.
Other Names:
  • speckle imager
Diagnostic test: Medoc Quantitative Sensory Testing

Quantitative sensory testing (QST) is a method through which sensory nerve function is quantitatively measured, based on responses of the subject. The peripheral sensory nervous system responds to specific stimuli of specific modality and intensity in a specific manner, which is well-known through many decades of research into human sensation. Thermal QST provides information about the function of small diameter unmyelinated (C fibers) and thinly myelinated (A-delta fibers) nerve fibers for which no nerve conduction test, or other objective tests exist.

Small fiber nerve damage can manifest itself in thermal hypoesthesia (raised perception thresholds) or hyperalgesia (lowered pain thresholds).

Other Names:
  • QST
Active Comparator: Crossover testing in participants with painful neuropathy (ZTlido 1.8% lidocaine patch)
History, physical, and neurological exam Nerve conduction study Medical record review of neuropathy history PROMIS pain severity and interference testing Brief pain inventory Norfolk quality of life questionnaire Quantitative sensory testing 3mm skin punch biopsy Diode laser testing of C:Aδ ratio Non-invasive speckle imaging ZTlido 1.8% lidocaine patch application to both feet for 7 days up to 12 hours per day.
Procedure: Diode Laser fiber type Selective Stimulator
-Each patient will have an A and C fiber stimulation. Stimulation will be performed on the dorsum of the foot using stimulation previously published parameters to elicit "burning pain," which is from activation of C-fibers and "pinprick" pain from A-fib
Other Names:
  • DLss
Diagnostic test: PeriCam PSI NR
It is a method that visualizes tissue blood perfusion in real time. LASCA provides new means to study the microcirculation in ways that were not possible in the past. PeriCam PSI System combines dynamic response and high spatial resolution in one instrument, providing both real-time graphs and video recordings of the tissue being studied. To further enhance its usability, dedicated application software, PIMSoft, has been developed.
Other Names:
  • speckle imager
Diagnostic test: Medoc Quantitative Sensory Testing

Quantitative sensory testing (QST) is a method through which sensory nerve function is quantitatively measured, based on responses of the subject. The peripheral sensory nervous system responds to specific stimuli of specific modality and intensity in a specific manner, which is well-known through many decades of research into human sensation. Thermal QST provides information about the function of small diameter unmyelinated (C fibers) and thinly myelinated (A-delta fibers) nerve fibers for which no nerve conduction test, or other objective tests exist.

Small fiber nerve damage can manifest itself in thermal hypoesthesia (raised perception thresholds) or hyperalgesia (lowered pain thresholds).

Other Names:
  • QST
Drug: ZTlido 1.8 % Topical System
ZTLI(diethylamino)-N-(2,6-dimethylphenyl), has an octanol:water partition ratio of 43 at pH 7.4. Each ZTLIDO contains 36 mg of lidocaine (18 mg per gram adhesive) in a non-aqueous base and also contains the following inactive ingredients: butylated hydroxytoluene, dipropylene glycol, isostearic acid, mineral oil, polyisobutylene, silicone dioxide, styrene/isoprene/styrene block copolymer, and terpene resin. DO (lidocaine topical system) 1.8% is a single-layer, drug-in-adhesive topical delivery system comprised of an adhesive material containing 36 mg lidocaine, which is applied to a pliable nonwoven cloth backing and covered with a polyethylene terephthalate film release liner. The release liner is removed prior to application to the skin. The size of ZTLIDO is 10 cm × 14 cm × 0.08 cm. Lidocaine, an amide local anesthetic, is chemically designated as acetamide, 2-
Placebo Comparator: Crossover testing in participants with painful neuropathy (placebo patch)
History, physical, and neurological exam Nerve conduction study Medical record review of neuropathy history PROMIS pain severity and interference testing Brief pain inventory Norfolk quality of life questionnaire Quantitative sensory testing 3mm skin punch biopsy Diode laser testing of C:Aδ ratio Non-invasive speckle imaging Placebo patch application to both feet for 7 days up to 12 hours per day.
Procedure: Diode Laser fiber type Selective Stimulator
-Each patient will have an A and C fiber stimulation. Stimulation will be performed on the dorsum of the foot using stimulation previously published parameters to elicit "burning pain," which is from activation of C-fibers and "pinprick" pain from A-fib
Other Names:
  • DLss
Diagnostic test: PeriCam PSI NR
It is a method that visualizes tissue blood perfusion in real time. LASCA provides new means to study the microcirculation in ways that were not possible in the past. PeriCam PSI System combines dynamic response and high spatial resolution in one instrument, providing both real-time graphs and video recordings of the tissue being studied. To further enhance its usability, dedicated application software, PIMSoft, has been developed.
Other Names:
  • speckle imager
Diagnostic test: Medoc Quantitative Sensory Testing

Quantitative sensory testing (QST) is a method through which sensory nerve function is quantitatively measured, based on responses of the subject. The peripheral sensory nervous system responds to specific stimuli of specific modality and intensity in a specific manner, which is well-known through many decades of research into human sensation. Thermal QST provides information about the function of small diameter unmyelinated (C fibers) and thinly myelinated (A-delta fibers) nerve fibers for which no nerve conduction test, or other objective tests exist.

Small fiber nerve damage can manifest itself in thermal hypoesthesia (raised perception thresholds) or hyperalgesia (lowered pain thresholds).

Other Names:
  • QST
Other: Inactive Topical System
Inactive, non-medicated topical system comprised of an adhesive material containing, which is applied to a pliable nonwoven cloth backing and covered with a polyethylene terephthalate film release liner. The release liner is removed prior to application to the skin. The size of the system is 10 cm × 14 cm × 0.08 cm.
Other Names:
  • placebo patch

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
CMi:Aδ ratio of amperage for sensory perception threshold following diode laser stimulation
Time Frame: 4 years
Participants' will report sensory threshold and pain threshold following diode laser stimulation to foot dorsum of ascending power as measured by amperage.
4 years
Area of neurogenic flare response (mm squared) following repetitive subthreshold diode laser stimulation.
Time Frame: 24 months
Foot dorsum skin will be repeatedly stimulated by diode laser and area of neurogenic flare measured using red blood cell reflectance using a speckle imager.
24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Utah

Collaborators

National Institute of Neurological Disorders and Stroke (NINDS)
National Institutes of Health (NIH)
Stanford University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 1, 2023

Primary Completion (Actual)

February 9, 2026

Study Completion (Actual)

February 9, 2026

Study Registration Dates

First Submitted

August 4, 2023

First Submitted That Met QC Criteria

September 5, 2023

First Posted (Actual)

September 8, 2023

Study Record Updates

Last Update Posted (Actual)

April 17, 2026

Last Update Submitted That Met QC Criteria

April 15, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DLss-R61/R33

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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