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The Potential Role of Sensory Testing, Skin Biopsy, and Functional Brain Imaging as Biomarkers in Chronic Pain Clinical Trials: IMMPACT Considerations

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    ∗ Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, Rochester, New York
    Shannon M. Smith
    Correspondence
    Address reprint requests to Shannon M. Smith, PhD, University of Rochester School of Medicine and Dentistry, Department of Anesthesiology, 601 Elmwood Ave, Box 604, Rochester, NY 14642.
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    ∗ Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, Rochester, New York
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    ∗ Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, Rochester, New York
    ,
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    † Departments of Neurology and Psychiatry, and Center for Human Experimental Therapeutics, University of Rochester School of Medicine and Dentistry, Rochester, New York
    Robert H. Dworkin
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    ∗ Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, Rochester, New York
    † Departments of Neurology and Psychiatry, and Center for Human Experimental Therapeutics, University of Rochester School of Medicine and Dentistry, Rochester, New York
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    ‡ Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington
    Dennis C. Turk
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    ‡ Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington
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    § Division of Neurological Pain Research and Therapy, Department of Neurology, University Medical Center Schleswig-Holstein, Kiel, Germany
    Ralf Baron
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    § Division of Neurological Pain Research and Therapy, Department of Neurology, University Medical Center Schleswig-Holstein, Kiel, Germany
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    ¶ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
    Michael Polydefkis
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    ¶ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
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    ‖ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
    Irene Tracey
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    ‖ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
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    ∗∗ Center for Pain and the Brain, Department of Anaesthesia, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
    David Borsook
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    ∗∗ Center for Pain and the Brain, Department of Anaesthesia, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
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    †† Department of Anesthesiology, Brigham & Women's Hospital, Boston, Massachusetts
    Robert R. Edwards
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    †† Department of Anesthesiology, Brigham & Women's Hospital, Boston, Massachusetts
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    ‡‡ Department of Anesthesiology and Internal Medicine, University of Michigan, Ann Arbor, Michigan
    Richard E. Harris
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    ‡‡ Department of Anesthesiology and Internal Medicine, University of Michigan, Ann Arbor, Michigan
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    §§ Departments of Psychology and Neuroscience, University of Colorado, Boulder, Boulder, Colorado
    Tor D. Wager
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    §§ Departments of Psychology and Neuroscience, University of Colorado, Boulder, Boulder, Colorado
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    ¶¶ Center for Sensory-Motor Interaction, Department of Health Sciences and Technology, School of Medicine, Aalborg University, Aalborg, Denmark
    Lars Arendt-Nielsen
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    ¶¶ Center for Sensory-Motor Interaction, Department of Health Sciences and Technology, School of Medicine, Aalborg University, Aalborg, Denmark
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    ‖‖ School of Pharmacy, University of Maryland, Baltimore, Maryland
    ,
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    ∗∗∗ LORA Group, LLC, Royal Oak, Maryland
    Laurie B. Burke
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    ‖‖ School of Pharmacy, University of Maryland, Baltimore, Maryland
    ∗∗∗ LORA Group, LLC, Royal Oak, Maryland
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    ††† Departments of Public Health, Anesthesiology, Medicine, and Molecular Physiology and Pharmacology, Tufts University School of Medicine, Boston, Massachusetts
    Daniel B. Carr
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    ††† Departments of Public Health, Anesthesiology, Medicine, and Molecular Physiology and Pharmacology, Tufts University School of Medicine, Boston, Massachusetts
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    ‡‡‡ Eli Lilly and Company, Indianapolis, Indiana
    Amy Chappell
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    ‡‡‡ Eli Lilly and Company, Indianapolis, Indiana
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    §§§ Departments of Epidemiology and Anesthesiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
    John T. Farrar
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    §§§ Departments of Epidemiology and Anesthesiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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    ¶¶¶ Department of Neurology, Harvard Medical School, Boston, Massachusetts
    Roy Freeman
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    ¶¶¶ Department of Neurology, Harvard Medical School, Boston, Massachusetts
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    ‖‖‖ Departments of Anesthesiology & Perioperative Medicine, Biomedical & Molecular Sciences, and Center of Neuroscience Studies, Queen's University, Kingston, Ontario, Canada
    Ian Gilron
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    ‖‖‖ Departments of Anesthesiology & Perioperative Medicine, Biomedical & Molecular Sciences, and Center of Neuroscience Studies, Queen's University, Kingston, Ontario, Canada
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    ∗∗∗∗ Pfizer, Inc, Cary, North Carolina
    Veeraindar Goli
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    ∗∗∗∗ Pfizer, Inc, Cary, North Carolina
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    †††† Janssen Research & Development, LLC, Titusville, New Jersey
    Juergen Haeussler
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    †††† Janssen Research & Development, LLC, Titusville, New Jersey
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    ‡‡‡‡ Department of Neurology & Danish Pain Research Center, Aarhus University, Aarhus, Denmark
    Troels Jensen
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    ‡‡‡‡ Department of Neurology & Danish Pain Research Center, Aarhus University, Aarhus, Denmark
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    §§§§ Analgesic Solutions, Natick, Massachusetts
    ,
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    ¶¶¶¶ Department of Anesthesiology, Tufts University School of Medicine, Boston, Massachusetts
    Nathaniel P. Katz
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    §§§§ Analgesic Solutions, Natick, Massachusetts
    ¶¶¶¶ Department of Anesthesiology, Tufts University School of Medicine, Boston, Massachusetts
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    ‖‖‖‖ Horizon Pharma, Inc, Lake Forest, Illinois
    Jeffrey Kent
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    ‖‖‖‖ Horizon Pharma, Inc, Lake Forest, Illinois
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    ∗∗∗∗∗ Collegium Pharmaceutical, Inc, Canton, Massachusetts
    Ernest A. Kopecky
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    ∗∗∗∗∗ Collegium Pharmaceutical, Inc, Canton, Massachusetts
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  • David A. Lee
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    ††††† Department of Anesthesiology, Duke University, Durham, North Carolina
    William Maixner
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    ††††† Department of Anesthesiology, Duke University, Durham, North Carolina
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    ‡‡‡‡‡ Neuromedicine Pain Management and Translational Pain Research, University of Rochester School of Medicine and Dentistry, Rochester, New York
    John D. Markman
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    ‡‡‡‡‡ Neuromedicine Pain Management and Translational Pain Research, University of Rochester School of Medicine and Dentistry, Rochester, New York
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    ∗∗ Center for Pain and the Brain, Department of Anaesthesia, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
    Justin C. McArthur
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    ∗∗ Center for Pain and the Brain, Department of Anaesthesia, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
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    † Departments of Neurology and Psychiatry, and Center for Human Experimental Therapeutics, University of Rochester School of Medicine and Dentistry, Rochester, New York
    ,
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    §§§§§ Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York
    Michael P. McDermott
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    † Departments of Neurology and Psychiatry, and Center for Human Experimental Therapeutics, University of Rochester School of Medicine and Dentistry, Rochester, New York
    §§§§§ Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York
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    ¶¶¶¶¶ Bristol-Myers Squibb, Princeton, New Jersey
    Lav Parvathenani
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    ¶¶¶¶¶ Bristol-Myers Squibb, Princeton, New Jersey
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    ‖‖‖‖‖ Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
    Srinivasa N. Raja
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    ‖‖‖‖‖ Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
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    ∗∗∗∗∗∗ Analgesic Concepts LLC, Arlington, Virginia
    Bob A. Rappaport
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    ∗∗∗∗∗∗ Analgesic Concepts LLC, Arlington, Virginia
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    †††††† Pain Research, Department of Surgery & Cancer, Imperial College, London, United Kingdom
    Andrew S.C. Rice
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    †††††† Pain Research, Department of Surgery & Cancer, Imperial College, London, United Kingdom
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    ‡‡‡‡‡‡ California Pacific Medical Center Research Institute, San Francisco, California
    Michael C. Rowbotham
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    ‡‡‡‡‡‡ California Pacific Medical Center Research Institute, San Francisco, California
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    §§§§§§ Aquila Consulting Group, LLC, Petaluma, California
    Jeffrey K. Tobias
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    §§§§§§ Aquila Consulting Group, LLC, Petaluma, California
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    ¶¶¶¶¶¶ Departments of Anesthesiology and Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
    Ajay D. Wasan
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    ¶¶¶¶¶¶ Departments of Anesthesiology and Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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    ‖‖‖‖‖‖ Division of Skin and Rheumatic Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland
    James Witter
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    ‖‖‖‖‖‖ Division of Skin and Rheumatic Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland
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  • Author Footnotes
    ∗ Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, Rochester, New York
    † Departments of Neurology and Psychiatry, and Center for Human Experimental Therapeutics, University of Rochester School of Medicine and Dentistry, Rochester, New York
    ‡ Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington
    § Division of Neurological Pain Research and Therapy, Department of Neurology, University Medical Center Schleswig-Holstein, Kiel, Germany
    ¶ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland
    ‖ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
    ∗∗ Center for Pain and the Brain, Department of Anaesthesia, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
    †† Department of Anesthesiology, Brigham & Women's Hospital, Boston, Massachusetts
    ‡‡ Department of Anesthesiology and Internal Medicine, University of Michigan, Ann Arbor, Michigan
    §§ Departments of Psychology and Neuroscience, University of Colorado, Boulder, Boulder, Colorado
    ¶¶ Center for Sensory-Motor Interaction, Department of Health Sciences and Technology, School of Medicine, Aalborg University, Aalborg, Denmark
    ‖‖ School of Pharmacy, University of Maryland, Baltimore, Maryland
    ∗∗∗ LORA Group, LLC, Royal Oak, Maryland
    ††† Departments of Public Health, Anesthesiology, Medicine, and Molecular Physiology and Pharmacology, Tufts University School of Medicine, Boston, Massachusetts
    ‡‡‡ Eli Lilly and Company, Indianapolis, Indiana
    §§§ Departments of Epidemiology and Anesthesiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
    ¶¶¶ Department of Neurology, Harvard Medical School, Boston, Massachusetts
    ‖‖‖ Departments of Anesthesiology & Perioperative Medicine, Biomedical & Molecular Sciences, and Center of Neuroscience Studies, Queen's University, Kingston, Ontario, Canada
    ∗∗∗∗ Pfizer, Inc, Cary, North Carolina
    †††† Janssen Research & Development, LLC, Titusville, New Jersey
    ‡‡‡‡ Department of Neurology & Danish Pain Research Center, Aarhus University, Aarhus, Denmark
    §§§§ Analgesic Solutions, Natick, Massachusetts
    ¶¶¶¶ Department of Anesthesiology, Tufts University School of Medicine, Boston, Massachusetts
    ‖‖‖‖ Horizon Pharma, Inc, Lake Forest, Illinois
    ∗∗∗∗∗ Collegium Pharmaceutical, Inc, Canton, Massachusetts
    ††††† Department of Anesthesiology, Duke University, Durham, North Carolina
    ‡‡‡‡‡ Neuromedicine Pain Management and Translational Pain Research, University of Rochester School of Medicine and Dentistry, Rochester, New York
    §§§§§ Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York
    ¶¶¶¶¶ Bristol-Myers Squibb, Princeton, New Jersey
    ‖‖‖‖‖ Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
    ∗∗∗∗∗∗ Analgesic Concepts LLC, Arlington, Virginia
    †††††† Pain Research, Department of Surgery & Cancer, Imperial College, London, United Kingdom
    ‡‡‡‡‡‡ California Pacific Medical Center Research Institute, San Francisco, California
    §§§§§§ Aquila Consulting Group, LLC, Petaluma, California
    ¶¶¶¶¶¶ Departments of Anesthesiology and Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
    ‖‖‖‖‖‖ Division of Skin and Rheumatic Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland
Published:February 28, 2017DOI:https://doi.org/10.1016/j.jpain.2017.02.429

      Highlights

      • No biomarkers to evaluate pain have been qualified for pain treatment trials.
      • Sensory testing, skin biopsy, and brain imaging have potential as pain biomarkers.
      • Further standardization and evidence of validity and reliability are needed.

      Abstract

      Valid and reliable biomarkers can play an important role in clinical trials as indicators of biological or pathogenic processes or as a signal of treatment response. Currently, there are no biomarkers for pain qualified by the U.S. Food and Drug Administration or the European Medicines Agency for use in clinical trials. This article summarizes an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting in which 3 potential biomarkers were discussed for use in the development of analgesic treatments: 1) sensory testing, 2) skin punch biopsy, and 3) brain imaging. The empirical evidence supporting the use of these tests is described within the context of the 4 categories of biomarkers: 1) diagnostic, 2) prognostic, 3) predictive, and 4) pharmacodynamic. Although sensory testing, skin punch biopsy, and brain imaging are promising tools for pain in clinical trials, additional evidence is needed to further support and standardize these tests for use as biomarkers in pain clinical trials.

      Perspective

      The applicability of sensory testing, skin biopsy, and brain imaging as diagnostic, prognostic, predictive, and pharmacodynamic biomarkers for use in analgesic treatment trials is considered. Evidence in support of their use and outlining problems is presented, as well as a call for further standardization and demonstrations of validity and reliability.

      Key words

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