DLss: Diode Laser as a Biomarker for Neuropathic Pain of Peripheral Origin.
Study Details
Study Description
Brief Summary
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.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
N/A |
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)
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
Study Design
Arms and Interventions
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:
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:
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:
|
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:
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:
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:
|
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:
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-
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:
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:
|
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:
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:
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:
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:
|
Outcome Measures
Primary Outcome Measures
- CMi:Aδ ratio of amperage for sensory perception threshold following diode laser stimulation [4 years]
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. [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.
Eligibility Criteria
Criteria
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)
-
Taking exclusionary medications related to lidocaine, or with anti-arrhythmic properties, such as tocainide or mexilitine.
-
Severe liver disease
-
People currently receiving chemotherapy.
-
Unable to complete protocol requirements in the judgement of the investigator.-
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Stanford University | Palo Alto | California | United States | 94305 |
2 | University of Utah | Salt Lake City | Utah | United States | 84132 |
Sponsors and Collaborators
- University of Utah
- Stanford University
- National Institutes of Health (NIH)
- National Institute of Neurological Disorders and Stroke (NINDS)
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
- A. Smith ML, J. Singleton. The diagnostic utility of nerve conduction studies and skin biopsy for diabetic neuropathy (DPN): a Bayesian analysis (S42.007). Neurology. Apr 2015;84.
- Anand P, Bley K. Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch. Br J Anaesth. 2011 Oct;107(4):490-502. doi: 10.1093/bja/aer260. Epub 2011 Aug 17.
- Argoff CE. New analgesics for neuropathic pain: the lidocaine patch. Clin J Pain. 2000 Jun;16(2 Suppl):S62-6. doi: 10.1097/00002508-200006001-00011.
- Backonja MM, Attal N, Baron R, Bouhassira D, Drangholt M, Dyck PJ, Edwards RR, Freeman R, Gracely R, Haanpaa MH, Hansson P, Hatem SM, Krumova EK, Jensen TS, Maier C, Mick G, Rice AS, Rolke R, Treede RD, Serra J, Toelle T, Tugnoli V, Walk D, Walalce MS, Ware M, Yarnitsky D, Ziegler D. Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus. Pain. 2013 Sep;154(9):1807-1819. doi: 10.1016/j.pain.2013.05.047. Epub 2013 Jun 3. Erratum In: Pain. 2014 Jan;155(1):205.
- Backryd E. Pain in the Blood? Envisioning Mechanism-Based Diagnoses and Biomarkers in Clinical Pain Medicine. Diagnostics (Basel). 2015 Mar 17;5(1):84-95. doi: 10.3390/diagnostics5010084.
- Bennett GJ, Liu GK, Xiao WH, Jin HW, Siau C. Terminal arbor degeneration--a novel lesion produced by the antineoplastic agent paclitaxel. Eur J Neurosci. 2011 May;33(9):1667-76. doi: 10.1111/j.1460-9568.2011.07652.x. Epub 2011 Mar 13.
- Beydoun A, Dyke DB, Morrow TJ, Casey KL. Topical capsaicin selectively attenuates heat pain and A delta fiber-mediated laser-evoked potentials. Pain. 1996 May-Jun;65(2-3):189-96. doi: 10.1016/0304-3959(95)00161-1.
- Bhattacharya A, Wickenden AD, Chaplan SR. Sodium channel blockers for the treatment of neuropathic pain. Neurotherapeutics. 2009 Oct;6(4):663-78. doi: 10.1016/j.nurt.2009.08.001.
- Bhupathiraju SN, Hu FB. Epidemiology of Obesity and Diabetes and Their Cardiovascular Complications. Circ Res. 2016 May 27;118(11):1723-35. doi: 10.1161/CIRCRESAHA.115.306825.
- Bickel A, Kramer HH, Hilz MJ, Birklein F, Neundorfer B, Schmelz M. Assessment of the neurogenic flare reaction in small-fiber neuropathies. Neurology. 2002 Sep 24;59(6):917-9. doi: 10.1212/wnl.59.6.917.
- Boger MS, Hulgan T, Haas DW, Mitchell V, Smith AG, Singleton JR, Peltier AC. Measures of small-fiber neuropathy in HIV infection. Auton Neurosci. 2012 Jul 2;169(1):56-61. doi: 10.1016/j.autneu.2012.04.001. Epub 2012 Apr 28.
- Brix Finnerup N, Hein Sindrup S, Staehelin Jensen T. Management of painful neuropathies. Handb Clin Neurol. 2013;115:279-90. doi: 10.1016/B978-0-444-52902-2.00017-5.
- Bromm B, Treede RD. Nerve fibre discharges, cerebral potentials and sensations induced by CO2 laser stimulation. Hum Neurobiol. 1984;3(1):33-40.
- Brooks KG, Kessler TL. Treatments for neuropathic pain. The Pharmaceutical Journal. 2017; 9(12). Epub 13 Sept 2017
- Brown JD, Saeed M, Do L, Braz J, Basbaum AI, Iadarola MJ, Wilson DM, Dillon WP. CT-guided injection of a TRPV1 agonist around dorsal root ganglia decreases pain transmission in swine. Sci Transl Med. 2015 Sep 16;7(305):305ra145. doi: 10.1126/scitranslmed.aac6589.
- Calderon E, Calderon-Seoane ME, Garcia-Hernandez R, Torres LM. 5% Lidocaine-medicated plaster for the treatment of chronic peripheral neuropathic pain: complex regional pain syndrome and other neuropathic conditions. J Pain Res. 2016 Oct 6;9:763-770. doi: 10.2147/JPR.S113517. eCollection 2016.
- Callaghan BC, Reynolds E, Banerjee M, Kerber KA, Skolarus LE, Burke JF. Longitudinal pattern of pain medication utilization in peripheral neuropathy patients. Pain. 2019 Mar;160(3):592-599. doi: 10.1097/j.pain.0000000000001439.
- Campbell JN, Meyer RA. Mechanisms of neuropathic pain. Neuron. 2006 Oct 5;52(1):77-92. doi: 10.1016/j.neuron.2006.09.021.
- Chevrier P, Vijayaragavan K, Chahine M. Differential modulation of Nav1.7 and Nav1.8 peripheral nerve sodium channels by the local anesthetic lidocaine. Br J Pharmacol. 2004 Jun;142(3):576-84. doi: 10.1038/sj.bjp.0705796. Epub 2004 May 17.
- Colloca L, Ludman T, Bouhassira D, Baron R, Dickenson AH, Yarnitsky D, Freeman R, Truini A, Attal N, Finnerup NB, Eccleston C, Kalso E, Bennett DL, Dworkin RH, Raja SN. Neuropathic pain. Nat Rev Dis Primers. 2017 Feb 16;3:17002. doi: 10.1038/nrdp.2017.2.
- Colloca L. The Placebo Effect in Pain Therapies. Annu Rev Pharmacol Toxicol. 2019 Jan 6;59:191-211. doi: 10.1146/annurev-pharmtox-010818-021542. Epub 2018 Sep 14.
- Control CfD. Non Opioid treatments for chronic pain: principles of chronic pain treatment.2019. Epub 6/12/2019.
- Cuellar JM, Manering NA, Klukinov M, Nemenov MI, Yeomans DC. Thermal nociceptive properties of trigeminal afferent neurons in rats. Mol Pain. 2010 Jul 7;6:39. doi: 10.1186/1744-8069-6-39.
- Davis KD, Aghaeepour N, Ahn AH, Angst MS, Borsook D, Brenton A, Burczynski ME, Crean C, Edwards R, Gaudilliere B, Hergenroeder GW, Iadarola MJ, Iyengar S, Jiang Y, Kong JT, Mackey S, Saab CY, Sang CN, Scholz J, Segerdahl M, Tracey I, Veasley C, Wang J, Wager TD, Wasan AD, Pelleymounter MA. Discovery and validation of biomarkers to aid the development of safe and effective pain therapeutics: challenges and opportunities. Nat Rev Neurol. 2020 Jul;16(7):381-400. doi: 10.1038/s41582-020-0362-2. Epub 2020 Jun 15.
- Devers A, Galer BS. Topical lidocaine patch relieves a variety of neuropathic pain conditions: an open-label study. Clin J Pain. 2000 Sep;16(3):205-8. doi: 10.1097/00002508-200009000-00005.
- DiBonaventura MD, Sadosky A, Concialdi K, Hopps M, Kudel I, Parsons B, Cappelleri JC, Hlavacek P, Alexander AH, Stacey BR, Markman JD, Farrar JT. The prevalence of probable neuropathic pain in the US: results from a multimodal general-population health survey. J Pain Res. 2017 Nov 1;10:2525-2538. doi: 10.2147/JPR.S127014. eCollection 2017.
- Diehr P, Chen L, Patrick D, Feng Z, Yasui Y. Reliability, effect size, and responsiveness of health status measures in the design of randomized and cluster-randomized trials. Contemp Clin Trials. 2005 Feb;26(1):45-58. doi: 10.1016/j.cct.2004.11.014. Epub 2005 Jan 27.
- Djouhri L, Koutsikou S, Fang X, McMullan S, Lawson SN. Spontaneous pain, both neuropathic and inflammatory, is related to frequency of spontaneous firing in intact C-fiber nociceptors. J Neurosci. 2006 Jan 25;26(4):1281-92. doi: 10.1523/JNEUROSCI.3388-05.2006.
- Donadio V, Liguori R. Microneurographic recording from unmyelinated nerve fibers in neurological disorders: an update. Clin Neurophysiol. 2015 Mar;126(3):437-45. doi: 10.1016/j.clinph.2014.10.009. Epub 2014 Oct 17.
- Dubin AE, Patapoutian A. Nociceptors: the sensors of the pain pathway. J Clin Invest. 2010 Nov;120(11):3760-72. doi: 10.1172/JCI42843. Epub 2010 Nov 1.
- Dusch M, Schley M, Rukwied R, Schmelz M. Rapid flare development evoked by current frequency-dependent stimulation analyzed by full-field laser perfusion imaging. Neuroreport. 2007 Jul 16;18(11):1101-5. doi: 10.1097/WNR.0b013e3281e72cff.
- Dworkin RH, Jensen MP, Gammaitoni AR, Olaleye DO, Galer BS. Symptom profiles differ in patients with neuropathic versus non-neuropathic pain. J Pain. 2007 Feb;8(2):118-26. doi: 10.1016/j.jpain.2006.06.005. Epub 2006 Sep 1. Erratum In: J Pain. 2007 Jun;8(6):531.
- Dyck PJ, Herrmann DN, Staff NP, Dyck PJ. Assessing decreased sensation and increased sensory phenomena in diabetic polyneuropathies. Diabetes. 2013 Nov;62(11):3677-86. doi: 10.2337/db13-0352.
- Eriksson KF, Nilsson H, Lindgarde F, Osterlin S, Dahlin LB, Lilja B, Rosen I, Sundkvist G. Diabetes mellitus but not impaired glucose tolerance is associated with dysfunction in peripheral nerves. Diabet Med. 1994 Apr;11(3):279-85. doi: 10.1111/j.1464-5491.1994.tb00272.x.
- FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource [Internet]. Silver Spring (MD): Food and Drug Administration (US); 2016-. Available from http://www.ncbi.nlm.nih.gov/books/NBK326791/
- Fillingim RB, Loeser JD, Baron R, Edwards RR. Assessment of Chronic Pain: Domains, Methods, and Mechanisms. J Pain. 2016 Sep;17(9 Suppl):T10-20. doi: 10.1016/j.jpain.2015.08.010.
- Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, Gilron I, Haanpaa M, Hansson P, Jensen TS, Kamerman PR, Lund K, Moore A, Raja SN, Rice AS, Rowbotham M, Sena E, Siddall P, Smith BH, Wallace M. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015 Feb;14(2):162-73. doi: 10.1016/S1474-4422(14)70251-0. Epub 2015 Jan 7.
- Fitridge R, Thompson M, editors. Mechanisms of Vascular Disease: A Reference Book for Vascular Specialists [Internet]. Adelaide (AU): University of Adelaide Press; 2011. No abstract available. Available from http://www.ncbi.nlm.nih.gov/books/NBK534260/
- Forstenpointner J, Naleschinski D, Wasner G, Hullemann P, Binder A, Baron R. Sensitized vasoactive C-nociceptors: key fibers in peripheral neuropathic pain. Pain Rep. 2019 Jan 18;4(1):e709. doi: 10.1097/PR9.0000000000000709. eCollection 2019 Jan-Feb.
- Foster-Palmer, S.C, Singleton, J.R., Revere, C., Marcus, R.L., Shakeri, M., Castillo, A., Shafi, S. 34-LB: Reliability of the UENS for Primary Care Neuropathy Screening. Diabetes. 2020;69. doi: 10.2337/db20-34-LB.
- Fruhstorfer H, Lindblom U, Schmidt WC. Method for quantitative estimation of thermal thresholds in patients. J Neurol Neurosurg Psychiatry. 1976 Nov;39(11):1071-5. doi: 10.1136/jnnp.39.11.1071.
- Galer BS, Jensen MP, Ma T, Davies PS, Rowbotham MC. The lidocaine patch 5% effectively treats all neuropathic pain qualities: results of a randomized, double-blind, vehicle-controlled, 3-week efficacy study with use of the neuropathic pain scale. Clin J Pain. 2002 Sep-Oct;18(5):297-301. doi: 10.1097/00002508-200209000-00004.
- Gammaitoni AR, Alvarez NA, Galer BS. Safety and tolerability of the lidocaine patch 5%, a targeted peripheral analgesic: a review of the literature. J Clin Pharmacol. 2003 Feb;43(2):111-7. doi: 10.1177/0091270002239817.
- Gorson KC, Ropper AH. Idiopathic distal small fiber neuropathy. Acta Neurol Scand. 1995 Nov;92(5):376-82. doi: 10.1111/j.1600-0404.1995.tb00150.x.
- Granovsky Y, Matre D, Sokolik A, Lorenz J, Casey KL. Thermoreceptive innervation of human glabrous and hairy skin: a contact heat evoked potential analysis. Pain. 2005 Jun;115(3):238-247. doi: 10.1016/j.pain.2005.02.017. Epub 2005 Apr 18.
- Greene DA, Sima AA, Stevens MJ, Feldman EL, Lattimer SA. Complications: neuropathy, pathogenetic considerations. Diabetes Care. 1992 Dec;15(12):1902-25. doi: 10.2337/diacare.15.12.1902.
- Greffrath W, Nemenov MI, Schwarz S, Baumgartner U, Vogel H, Arendt-Nielsen L, Treede RD. Inward currents in primary nociceptive neurons of the rat and pain sensations in humans elicited by infrared diode laser pulses. Pain. 2002 Sep;99(1-2):145-55. doi: 10.1016/s0304-3959(02)00071-4.
- Gudin J, Nalamachu S. Utility of lidocaine as a topical analgesic and improvements in patch delivery systems. Postgrad Med. 2020 Jan;132(1):28-36. doi: 10.1080/00325481.2019.1702296. Epub 2020 Jan 3.
- Hans GH, Robert DN, Van Maldeghem KN. Treatment of an acute severe central neuropathic pain syndrome by topical application of lidocaine 5% patch: a case report. Spinal Cord. 2008 Apr;46(4):311-3. doi: 10.1038/sj.sc.3102098. Epub 2007 Jul 3.
- Haroutounian S, Nikolajsen L, Bendtsen TF, Finnerup NB, Kristensen AD, Hasselstrom JB, Jensen TS. Primary afferent input critical for maintaining spontaneous pain in peripheral neuropathy. Pain. 2014 Jul;155(7):1272-1279. doi: 10.1016/j.pain.2014.03.022. Epub 2014 Apr 2.
- Havlik RJ, Blackwelder WC, Kaslow R, Castelli W. Unlikely association between clinically apparent herpesvirus infection and coronary incidence at older ages. The Framingham Heart Study. Arteriosclerosis. 1989 Nov-Dec;9(6):877-80. doi: 10.1161/01.atv.9.6.877.
- Hawker GA, Mian S, Kendzerska T, French M. Measures of adult pain: Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res (Hoboken). 2011 Nov;63 Suppl 11:S240-52. doi: 10.1002/acr.20543. No abstract available.
- Hofseth LJ. Getting rigorous with scientific rigor. Carcinogenesis. 2018 Jan 12;39(1):21-25. doi: 10.1093/carcin/bgx085. No abstract available.
- Hovaguimian A, Gibbons CH. Diagnosis and treatment of pain in small-fiber neuropathy. Curr Pain Headache Rep. 2011 Jun;15(3):193-200. doi: 10.1007/s11916-011-0181-7.
- Hulicius E. aKV. Semiconductor lasers for medical applications. Lasers for Medical Applications Diagnostics, Therapy and Surgery. Woodhead Publishing Series in Electronic and Optical Materials: Elsevier BV; 2013. p. 222-50.
- JM. B. Pain as Human Experience: An Anthropological Perspective. JAMA. 1993; 270(8):998-9. doi:10.1001/jama.1993.03510080104042.
- Kalliomaki M, Kieseritzky JV, Schmidt R, Hagglof B, Karlsten R, Sjogren N, Albrecht P, Gee L, Rice F, Wiig M, Schmelz M, Gordh T. Structural and functional differences between neuropathy with and without pain? Exp Neurol. 2011 Oct;231(2):199-206. doi: 10.1016/j.expneurol.2011.05.019. Epub 2011 Jun 13.
- Kankel J, Obreja O, Kleggetveit IP, Schmidt R, Jorum E, Schmelz M, Namer B. Differential effects of low dose lidocaine on C-fiber classes in humans. J Pain. 2012 Dec;13(12):1232-41. doi: 10.1016/j.jpain.2012.09.008.
- Karlsson P, Hincker AM, Jensen TS, Freeman R, Haroutounian S. Structural, functional, and symptom relations in painful distal symmetric polyneuropathies: a systematic review. Pain. 2019 Feb;160(2):286-297. doi: 10.1097/j.pain.0000000000001381.
- Katz NP, Gammaitoni AR, Davis MW, Dworkin RH; Lidoderm Patch Study Group. Lidocaine patch 5% reduces pain intensity and interference with quality of life in patients with postherpetic neuralgia: an effectiveness trial. Pain Med. 2002 Dec;3(4):324-32. doi: 10.1046/j.1526-4637.2002.02050.x.
- Kennedy WR, Vanhove GF, Lu SP, Tobias J, Bley KR, Walk D, Wendelschafer-Crabb G, Simone DA, Selim MM. A randomized, controlled, open-label study of the long-term effects of NGX-4010, a high-concentration capsaicin patch, on epidermal nerve fiber density and sensory function in healthy volunteers. J Pain. 2010 Jun;11(6):579-87. doi: 10.1016/j.jpain.2009.09.019. Epub 2010 Apr 18.
- Kirillova I, Teliban A, Gorodetskaya N, Grossmann L, Bartsch F, Rausch VH, Struck M, Tode J, Baron R, Janig W. Effect of local and intravenous lidocaine on ongoing activity in injured afferent nerve fibers. Pain. 2011 Jul;152(7):1562-1571. doi: 10.1016/j.pain.2011.02.046. Epub 2011 Apr 6.
- Kleggetveit IP, Namer B, Schmidt R, Helas T, Ruckel M, Orstavik K, Schmelz M, Jorum E. High spontaneous activity of C-nociceptors in painful polyneuropathy. Pain. 2012 Oct;153(10):2040-2047. doi: 10.1016/j.pain.2012.05.017.
- Kodaira M, Inui K, Kakigi R. Evaluation of nociceptive Adelta- and C-fiber dysfunction with lidocaine using intraepidermal electrical stimulation. Clin Neurophysiol. 2014 Sep;125(9):1870-7. doi: 10.1016/j.clinph.2014.01.009. Epub 2014 Jan 28.
- Krumova EK, Zeller M, Westermann A, Maier C. Lidocaine patch (5%) produces a selective, but incomplete block of Adelta and C fibers. Pain. 2012 Feb;153(2):273-280. doi: 10.1016/j.pain.2011.08.020. Epub 2011 Oct 11.
- Leiser SC, Dunlop J, Bowlby MR, Devilbiss DM. Aligning strategies for using EEG as a surrogate biomarker: a review of preclinical and clinical research. Biochem Pharmacol. 2011 Jun 15;81(12):1408-21. doi: 10.1016/j.bcp.2010.10.002. Epub 2010 Oct 19.
- Lennertz RC, Medler KA, Bain JL, Wright DE, Stucky CL. Impaired sensory nerve function and axon morphology in mice with diabetic neuropathy. J Neurophysiol. 2011 Aug;106(2):905-14. doi: 10.1152/jn.01123.2010. Epub 2011 Jun 8.
- Light AR. "Nocifensor" system re-revisited. Focus on "Two types of C nociceptor in human skin and their behavior in areas of capaicin-induced secondary hyperalgesia". J Neurophysiol. 2004 Jun;91(6):2401-3. doi: 10.1152/jn.00090.2004. No abstract available.
- Lind AL, Wu D, Freyhult E, Bodolea C, Ekegren T, Larsson A, Gustafsson MG, Katila L, Bergquist J, Gordh T, Landegren U, Kamali-Moghaddam M. A Multiplex Protein Panel Applied to Cerebrospinal Fluid Reveals Three New Biomarker Candidates in ALS but None in Neuropathic Pain Patients. PLoS One. 2016 Feb 25;11(2):e0149821. doi: 10.1371/journal.pone.0149821. eCollection 2016.
- Lynn B, Schutterle S, Pierau FK. The vasodilator component of neurogenic inflammation is caused by a special subclass of heat-sensitive nociceptors in the skin of the pig. J Physiol. 1996 Jul 15;494 ( Pt 2)(Pt 2):587-93. doi: 10.1113/jphysiol.1996.sp021516.
- Manchikanti L, Helm S 2nd, Fellows B, Janata JW, Pampati V, Grider JS, Boswell MV. Opioid epidemic in the United States. Pain Physician. 2012 Jul;15(3 Suppl):ES9-38.
- McCarberg BH, Billington R. Consequences of neuropathic pain: quality-of-life issues and associated costs. Am J Manag Care. 2006 Jun;12(9 Suppl):S263-8.
- McCormack HM, Horne DJ, Sheather S. Clinical applications of visual analogue scales: a critical review. Psychol Med. 1988 Nov;18(4):1007-19. doi: 10.1017/s0033291700009934.
- Meier T, Wasner G, Faust M, Kuntzer T, Ochsner F, Hueppe M, Bogousslavsky J, Baron R. Efficacy of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind, placebo-controlled study. Pain. 2003 Nov;106(1-2):151-8. doi: 10.1016/s0304-3959(03)00317-8.
- Mills EJ, Chan AW, Wu P, Vail A, Guyatt GH, Altman DG. Design, analysis, and presentation of crossover trials. Trials. 2009 Apr 30;10:27. doi: 10.1186/1745-6215-10-27.
- Mitchell K, Bates BD, Keller JM, Lopez M, Scholl L, Navarro J, Madian N, Haspel G, Nemenov MI, Iadarola MJ. Ablation of rat TRPV1-expressing Adelta/C-fibers with resiniferatoxin: analysis of withdrawal behaviors, recovery of function and molecular correlates. Mol Pain. 2010 Dec 17;6:94. doi: 10.1186/1744-8069-6-94.
- Mitchell K, Lebovitz EE, Keller JM, Mannes AJ, Nemenov MI, Iadarola MJ. Nociception and inflammatory hyperalgesia evaluated in rodents using infrared laser stimulation after Trpv1 gene knockout or resiniferatoxin lesion. Pain. 2014 Apr;155(4):733-745. doi: 10.1016/j.pain.2014.01.007. Epub 2014 Jan 13.
- Moeller-Bertram T, Schilling JM, Backonja MM, Nemenov MI. Sensory small fiber function differentially assessed with diode laser (DL) quantitative sensory testing (QST) in painful neuropathy (PN). Pain Med. 2013 Mar;14(3):417-21. doi: 10.1111/pme.12049. Epub 2013 Feb 22.
- Mu A, Weinberg E, Moulin DE, Clarke H. Pharmacologic management of chronic neuropathic pain: Review of the Canadian Pain Society consensus statement. Can Fam Physician. 2017 Nov;63(11):844-852.
- Najib U, Bashir S, Edwards D, Rotenberg A, Pascual-Leone A. Transcranial brain stimulation: clinical applications and future directions. Neurosurg Clin N Am. 2011 Apr;22(2):233-51, ix. doi: 10.1016/j.nec.2011.01.002.
- Nemenov MIN, B.; Schmidt, R.; Kleggetveit, I.P.; Backonja M.; E., Jorum E.; Schmelz M, editors. Heating of deeper skin layers might detect spontaneously active heat-sensitized nociceptors. Neuroscience; 2015; Chicago.
- Nolano M, Simone DA, Wendelschafer-Crabb G, Johnson T, Hazen E, Kennedy WR. Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain sensation. Pain. 1999 May;81(1-2):135-45. doi: 10.1016/s0304-3959(99)00007-x.
- Novella SP, Inzucchi SE, Goldstein JM. The frequency of undiagnosed diabetes and impaired glucose tolerance in patients with idiopathic sensory neuropathy. Muscle Nerve. 2001 Sep;24(9):1229-31. doi: 10.1002/mus.1137.
- Nwagwu CD, Sarris C, Tao YX, Mammis A. Biomarkers for Chronic Neuropathic Pain and their Potential Application in Spinal Cord Stimulation: A Review. Transl Perioper Pain Med. 2016;1(3):33-38.
- Obreja O, Hirth M, Turnquist B, Rukwied R, Ringkamp M, Schmelz M. The differential effects of two sodium channel modulators on the conductive properties of C-fibers in pig skin in vivo. Anesth Analg. 2012 Sep;115(3):560-71. doi: 10.1213/ANE.0b013e3182542843. Epub 2012 May 10.
- Obrosova IG. Diabetic painful and insensate neuropathy: pathogenesis and potential treatments. Neurotherapeutics. 2009 Oct;6(4):638-47. doi: 10.1016/j.nurt.2009.07.004.
- O'Connor AB. Neuropathic pain: quality-of-life impact, costs and cost effectiveness of therapy. Pharmacoeconomics. 2009;27(2):95-112. doi: 10.2165/00019053-200927020-00002.
- Orstavik K, Namer B, Schmidt R, Schmelz M, Hilliges M, Weidner C, Carr RW, Handwerker H, Jorum E, Torebjork HE. Abnormal function of C-fibers in patients with diabetic neuropathy. J Neurosci. 2006 Nov 1;26(44):11287-94. doi: 10.1523/JNEUROSCI.2659-06.2006.
- Park CH, Jung SH, Han CG. Effect of intravenous lidocaine on the neuropathic pain of failed back surgery syndrome. Korean J Pain. 2012 Apr;25(2):94-8. doi: 10.3344/kjp.2012.25.2.94. Epub 2012 Apr 4.
- Patel BK, Wendlandt BN, Wolfe KS, Patel SB, Doman ER, Pohlman AS, Hall JB, Kress JP. Comparison of Two Lidocaine Administration Techniques on Perceived Pain From Bedside Procedures: A Randomized Clinical Trial. Chest. 2018 Oct;154(4):773-780. doi: 10.1016/j.chest.2018.04.018. Epub 2018 Apr 24.
- Peltier A, Goutman SA, Callaghan BC. Painful diabetic neuropathy. BMJ. 2014 May 6;348:g1799. doi: 10.1136/bmj.g1799. Erratum In: BMJ. 2014;348:g3440.
- Pereira MP, Muhl S, Pogatzki-Zahn EM, Agelopoulos K, Stander S. Intraepidermal Nerve Fiber Density: Diagnostic and Therapeutic Relevance in the Management of Chronic Pruritus: a Review. Dermatol Ther (Heidelb). 2016 Dec;6(4):509-517. doi: 10.1007/s13555-016-0146-1. Epub 2016 Oct 11.
- Persaud N, Strichartz GR. Micromolar lidocaine selectively blocks propagating ectopic impulses at a distance from their site of origin. Pain. 2002 Sep;99(1-2):333-40. doi: 10.1016/s0304-3959(02)00163-x.
- Pickering G, Martin E, Tiberghien F, Delorme C, Mick G. Localized neuropathic pain: an expert consensus on local treatments. Drug Des Devel Ther. 2017 Sep 13;11:2709-2718. doi: 10.2147/DDDT.S142630. eCollection 2017.
- Rage M, Van Acker N, Facer P, Shenoy R, Knaapen MW, Timmers M, Streffer J, Anand P, Meert T, Plaghki L. The time course of CO2 laser-evoked responses and of skin nerve fibre markers after topical capsaicin in human volunteers. Clin Neurophysiol. 2010 Aug;121(8):1256-66. doi: 10.1016/j.clinph.2010.02.159. Epub 2010 Mar 26.
- Raman R. Statistical methods in handling placebo effect. Int Rev Neurobiol. 2020;153:103-120. doi: 10.1016/bs.irn.2020.04.004. Epub 2020 Jun 9.
- Rose M, Bjorner JB, Gandek B, Bruce B, Fries JF, Ware JE Jr. The PROMIS Physical Function item bank was calibrated to a standardized metric and shown to improve measurement efficiency. J Clin Epidemiol. 2014 May;67(5):516-26. doi: 10.1016/j.jclinepi.2013.10.024.
- Rose MA, Kam PC. Gabapentin: pharmacology and its use in pain management. Anaesthesia. 2002 May;57(5):451-62. doi: 10.1046/j.0003-2409.2001.02399.x.
- Rowbotham MC, Davies PS, Verkempinck C, Galer BS. Lidocaine patch: double-blind controlled study of a new treatment method for post-herpetic neuralgia. Pain. 1996 Apr;65(1):39-44. doi: 10.1016/0304-3959(95)00146-8.
- Safikhani S, Gries KS, Trudeau JJ, Reasner D, Rudell K, Coons SJ, Bush EN, Hanlon J, Abraham L, Vernon M. Response scale selection in adult pain measures: results from a literature review. J Patient Rep Outcomes. 2018 Sep 6;2:40. doi: 10.1186/s41687-018-0053-6. eCollection 2017.
- Sauerstein K, Klede M, Hilliges M, Schmelz M. Electrically evoked neuropeptide release and neurogenic inflammation differ between rat and human skin. J Physiol. 2000 Dec 15;529 Pt 3(Pt 3):803-10. doi: 10.1111/j.1469-7793.2000.00803.x.
- Schley M, Bayram A, Rukwied R, Dusch M, Konrad C, Benrath J, Geber C, Birklein F, Hagglof B, Sjogren N, Gee L, Albrecht PJ, Rice FL, Schmelz M. Skin innervation at different depths correlates with small fibre function but not with pain in neuropathic pain patients. Eur J Pain. 2012 Nov;16(10):1414-25. doi: 10.1002/j.1532-2149.2012.00157.x. Epub 2012 May 3.
- Schmelz M, Michael K, Weidner C, Schmidt R, Torebjork HE, Handwerker HO. Which nerve fibers mediate the axon reflex flare in human skin? Neuroreport. 2000 Feb 28;11(3):645-8. doi: 10.1097/00001756-200002280-00041.
- Schmelz M, Schmidt R. Microneurographic single-unit recordings to assess receptive properties of afferent human C-fibers. Neurosci Lett. 2010 Feb 19;470(3):158-61. doi: 10.1016/j.neulet.2009.05.064. Epub 2009 May 28.
- Schmidt R, Schmelz M, Weidner C, Handwerker HO, Torebjork HE. Innervation territories of mechano-insensitive C nociceptors in human skin. J Neurophysiol. 2002 Oct;88(4):1859-66. doi: 10.1152/jn.2002.88.4.1859.
- Schwarz GE. Estimating the dimension of a model. Annals of Statistics. 1978;6(2):461-4.
- Serra J, Bostock H, Sola R, Aleu J, Garcia E, Cokic B, Navarro X, Quiles C. Microneurographic identification of spontaneous activity in C-nociceptors in neuropathic pain states in humans and rats. Pain. 2012 Jan;153(1):42-55. doi: 10.1016/j.pain.2011.08.015. Epub 2011 Oct 10.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020 Jan;70(1):7-30. doi: 10.3322/caac.21590. Epub 2020 Jan 8.
- Singleton JR, Bixby B, Russell JW, Feldman EL, Peltier A, Goldstein J, Howard J, Smith AG. The Utah Early Neuropathy Scale: a sensitive clinical scale for early sensory predominant neuropathy. J Peripher Nerv Syst. 2008 Sep;13(3):218-27. doi: 10.1111/j.1529-8027.2008.00180.x.
- Singleton JR, Marcus RL, Jackson JE, K Lessard M, Graham TE, Smith AG. Exercise increases cutaneous nerve density in diabetic patients without neuropathy. Ann Clin Transl Neurol. 2014 Oct;1(10):844-9. doi: 10.1002/acn3.125. Epub 2014 Oct 12.
- Singleton JR, Marcus RL, Lessard MK, Jackson JE, Smith AG. Supervised exercise improves cutaneous reinnervation capacity in metabolic syndrome patients. Ann Neurol. 2015 Jan;77(1):146-53. doi: 10.1002/ana.24310. Epub 2014 Dec 4.
- Smith AG, Howard JR, Kroll R, Ramachandran P, Hauer P, Singleton JR, McArthur J. The reliability of skin biopsy with measurement of intraepidermal nerve fiber density. J Neurol Sci. 2005 Jan 15;228(1):65-9. doi: 10.1016/j.jns.2004.09.032. Epub 2004 Nov 5.
- Smith AG, Lessard M, Reyna S, Doudova M, Singleton JR. The diagnostic utility of Sudoscan for distal symmetric peripheral neuropathy. J Diabetes Complications. 2014 Jul-Aug;28(4):511-6. doi: 10.1016/j.jdiacomp.2014.02.013. Epub 2014 Mar 6.
- Stewart WF, Ricci JA, Chee E, Hirsch AG, Brandenburg NA. Lost productive time and costs due to diabetes and diabetic neuropathic pain in the US workforce. J Occup Environ Med. 2007 Jun;49(6):672-9. doi: 10.1097/JOM.0b013e318065b83a.
- Stino AM, Smith AG. Peripheral neuropathy in prediabetes and the metabolic syndrome. J Diabetes Investig. 2017 Sep;8(5):646-655. doi: 10.1111/jdi.12650. Epub 2017 May 3.
- Tavee J, Zhou L. Small fiber neuropathy: A burning problem. Cleve Clin J Med. 2009 May;76(5):297-305. doi: 10.3949/ccjm.76a.08070.
- Tillman DB, Treede RD, Meyer RA, Campbell JN. Response of C fibre nociceptors in the anaesthetized monkey to heat stimuli: correlation with pain threshold in humans. J Physiol. 1995 Jun 15;485 ( Pt 3)(Pt 3):767-74. doi: 10.1113/jphysiol.1995.sp020767.
- Tracey I, Woolf CJ, Andrews NA. Composite Pain Biomarker Signatures for Objective Assessment and Effective Treatment. Neuron. 2019 Mar 6;101(5):783-800. doi: 10.1016/j.neuron.2019.02.019.
- Treede RD, Meyer RA, Raja SN, Campbell JN. Evidence for two different heat transduction mechanisms in nociceptive primary afferents innervating monkey skin. J Physiol. 1995 Mar 15;483 ( Pt 3)(Pt 3):747-58. doi: 10.1113/jphysiol.1995.sp020619.
- Tzabazis A, Klyukinov M, Manering N, Nemenov MI, Shafer SL, Yeomans DC. Differential activation of trigeminal C or Adelta nociceptors by infrared diode laser in rats: behavioral evidence. Brain Res. 2005 Mar 10;1037(1-2):148-56. doi: 10.1016/j.brainres.2005.01.019.
- van der Miesen MM, Lindquist MA, Wager TD. Neuroimaging-based biomarkers for pain: state of the field and current directions. Pain Rep. 2019 Aug 7;4(4):e751. doi: 10.1097/PR9.0000000000000751. eCollection 2019 Jul-Aug.
- Veldhuijzen DS, Nemenov MI, Keaser M, Zhuo J, Gullapalli RP, Greenspan JD. Differential brain activation associated with laser-evoked burning and pricking pain: An event-related fMRI study. Pain. 2009 Jan;141(1-2):104-13. doi: 10.1016/j.pain.2008.10.027. Epub 2008 Dec 5.
- Verbeke, G. Linear Mixed Models for Longitudinal Data. In: Linear Mixed Models in Practice. Lecture Notes in Statistics, vol 126. Springer, New York, NY. 1997; doi: 10.1007/978-1-4612-2294-1_3
- Visser NA, Vrancken AF, van der Schouw YT, van den Berg LH, Notermans NC. Chronic idiopathic axonal polyneuropathy is associated with the metabolic syndrome. Diabetes Care. 2013 Apr;36(4):817-22. doi: 10.2337/dc12-0469. Epub 2012 Nov 30.
- von Hehn CA, Baron R, Woolf CJ. Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Neuron. 2012 Feb 23;73(4):638-52. doi: 10.1016/j.neuron.2012.02.008.
- Weidner C, Schmelz M, Schmidt R, Hansson B, Handwerker HO, Torebjork HE. Functional attributes discriminating mechano-insensitive and mechano-responsive C nociceptors in human skin. J Neurosci. 1999 Nov 15;19(22):10184-90. doi: 10.1523/JNEUROSCI.19-22-10184.1999.
- Windebank AJ, Grisold W. Chemotherapy-induced neuropathy. J Peripher Nerv Syst. 2008 Mar;13(1):27-46. doi: 10.1111/j.1529-8027.2008.00156.x.
- Wolf S, Barton D, Kottschade L, Grothey A, Loprinzi C. Chemotherapy-induced peripheral neuropathy: prevention and treatment strategies. Eur J Cancer. 2008 Jul;44(11):1507-15. doi: 10.1016/j.ejca.2008.04.018. Epub 2008 Jun 18.
- Wulff EA, Wang AK, Simpson DM. HIV-associated peripheral neuropathy: epidemiology, pathophysiology and treatment. Drugs. 2000 Jun;59(6):1251-60. doi: 10.2165/00003495-200059060-00005.
- Xiao WH, Bennett GJ. Chemotherapy-evoked neuropathic pain: Abnormal spontaneous discharge in A-fiber and C-fiber primary afferent neurons and its suppression by acetyl-L-carnitine. Pain. 2008 Apr;135(3):262-270. doi: 10.1016/j.pain.2007.06.001. Epub 2007 Jul 30.
- Yarnitsky D, Sprecher E, Zaslansky R, Hemli JA. Heat pain thresholds: normative data and repeatability. Pain. 1995 Mar;60(3):329-32. doi: 10.1016/0304-3959(94)00132-x.
- Younger J, McCue R, Mackey S. Pain outcomes: a brief review of instruments and techniques. Curr Pain Headache Rep. 2009 Feb;13(1):39-43. doi: 10.1007/s11916-009-0009-x.
- Zelman DC, Gore M, Dukes E, Tai KS, Brandenburg N. Validation of a modified version of the brief pain inventory for painful diabetic peripheral neuropathy. J Pain Symptom Manage. 2005 Apr;29(4):401-10. doi: 10.1016/j.jpainsymman.2004.06.018.
- Zhang J, Cavanaugh DJ, Nemenov MI, Basbaum AI. The modality-specific contribution of peptidergic and non-peptidergic nociceptors is manifest at the level of dorsal horn nociresponsive neurons. J Physiol. 2013 Feb 15;591(4):1097-110. doi: 10.1113/jphysiol.2012.242115. Epub 2012 Dec 24.
- DLss-R61/R33