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

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

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.

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) 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: Baseline neuropathic pain evaluation. Each participant will be screened in clinic, then record daily pain severity for 7 days. 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. A 7-day wash out period without treatment. 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

Response biomarker set-up and optimization in Healthy Subjects Examination of the relationship between Response Biomarker measures and severity of neuropathic pain in patients with peripheral neuropathy. Evaluate the the Response Biomarker using lidocaine patch as a peripherally acting neuropathic pain agents

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

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

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.

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.

-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

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-

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.

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).

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.

Participants' will report sensory threshold and pain threshold following diode laser stimulation to foot dorsum of ascending power as measured by amperage.

Area of neurogenic flare response (mm squared) following repetitive subthreshold diode laser stimulation.

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.

Inclusion Criteria: Inclusion criteria for Objective 1 (Stanford) 18 -70 years of age no complaints of peripheral neuropathy or other foot pain no medical history of disease or medication use associated with peripheral neuropathy (e.g. diabetes) no known allergy to lidocaine Inclusion Criteria for Objective 2 . 18 years of age and older 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 Objective 3 18 years of age and older Length dependent, sensory predominant, peripheral neuropathy from any non-acute acquired cause (e.g. diabetes, pre-diabetes, chemotherapy induced) . Pain rating on Visual Analog Scale (VAS) > 30mm Exclusion Criteria: Exclusion criteria Objective 1 (Stanford) complaints of peripheral neuropathy or other foot pain medical history of disease or medication use associated with peripheral neuropathy (e.g. diabetes) known allergy to lidocaine or other para-aminobenzioc acid derivative (ie: procaine, tetracaine, benzocaine) Exclusion Criteria Objective 2 and 3 Acute peripheral neuropathy (e.g. Guillain Barre Syndrome, glucose correction neuropathy) because of concerns for stability of neuropathic pain over the period of study participation. Bleeding diathesis, or history of severe bleeding with skin wounds. known allergy to lidocaine or other para-aminobenzioc acid derivative (ie: procaine, tetracaine, benzocaine) 4. Taking exclusionary medications related to lidocaine, or with anti-arrhythmic properties, such as tocainide or mexilitine. 5. Severe liver disease 6. People currently receiving chemotherapy. 7. Unable to complete protocol requirements in the judgement of the investigator.-

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