Placebo responses represent a substantial source of "noise" in clinical trials. Examination of inter-individual differences in the function of placebo responsive mechanisms, and potential surrogates (biomarkers) would help inform the sources of variability in clinical studies in an objective, mechanistic fashion. The formation of biologica placebo effects also represents a resiliency mechanism, uncovered by the cognitive emotional integration of the expectations created by the treating environment. As such, delineation of these processes would point to biological targets that have not been contemplated in traditional drug or treatment development. Endogenous opioid mechanisms have been centrally implicated in the formation of placebo analgesic effects for more than three-decades, but their function has not been systematically studied in clinical samples. This application examines the integrity of the endogenous opioid system in a sample of patients diagnosed with fibromyalgia (FM), a persistent pain syndrome with moderate placebo responses. We will utilize positron emission tomography (PET) and a selective ?-opioid receptor radiotracer to acquire objective molecular measures known to be associated with the formation of placebo analgesic effects in clinical and experimental samples. Measures of ?-opioid receptor (?OR) availability at baseline and the activation of this neurotransmitter system in response to a releasing challenge (intravenous placebo with expectation of analgesia) will be examined against treatment response measures in what effectively represents a within- subject, randomized, cross-over trial of placebo pills wit and without expectations of activity. We will utilize non-deceptive consent methodology, following current ethical recommendations and consistent with ongoing studies in our laboratory. It is proposed that baseline ?OR availability in vivo and the capacity to activate this neurotransmitter system in the context of positive expectations of improvement experimentally created during scanning and by the administration of placebo during the trial, will be associated with treatment response in FM patients. In the spirit of clinical applicability, these mechanistic, molecular imaging studies of predictors of treatment response in FM will be complemented by the examination of simpler biomarkers. The selected markers have been found associated with endogenous opioid system function, and their predictive value, alone and in combination, will be examined as potential predictors of so-called "non-specific" treatment responses. This proposal assembles a comprehensive team of clinicians and scientists with specialized and complementary expertise, and substantial track records in molecular imaging, chronic pain, FM and clinical trials that is uniquely positioned to manage and complete the studies proposed. It addresses a severe health problem, chronic pain, and a substantial source of variability in clinical studies, biological placebo effects, which has not been systematically studied at a mechanistic level in clinical samples. The data acquired will also point to novel treatment targets not addressed in traditional drug discovery strategies.

Public Health Relevance

Chronic pain represents a very substantial health problem. In spite of the severe individual and societal consequences of persistent pain, substantial placebo effects are observed in clinical trials that obscure the effects of potentially active drugs, This proposal utilizes molecular neuroimaging technology and simpler, clinically applicable, potential biomarkers to examine inter-individual variations in the function of the endogenous opioid system, a principal mechanism mediating endogenous analgesia and placebo analgesic responses. Those individual variations will then be related to treatment response in fibromyalgia syndrome, a prototypical persistent pain condition with moderate placebo responses.

National Institute of Health (NIH)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Khalsa, Partap Singh
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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