Pain inhibits pain: Conditioned pain modulation (CPM)

Abstract

Conditioned pain modulation (CPM), also termed as the diffuse noxious inhibitory controls (DNIC), is a kind of endogenous pain inhibitory modulation. It refers to the physiological phenomenon that subjective perception of a nociceptive stimulus (i.e., test stimulus) can be suppressed by another painful stimulus (i.e., conditioning stimulus) delivered to a body area far away from the stimulus site of test stimulus. Individual CPM efficiency is defined as the conditioning stimulus induced suppression of subjective pain perception of the test stimulus. Previous studies have showed that many types of chronic pain patients are characterized as deficts of CPM function, and CPM efficiency of patients could even predict the risk of developing chronic pain, suggesting possible clincial applications of CPM. However, since the underlying mechanisms of CPM are still not very clear, various factors could influence individual CPM efficiency, and the approaches of evaluting CPM effiency are even not consistent, the applications of CPM in clincial practice are limited and sluggish. For a better understanding of CPM process and an advancement CPM-related clincial applications, the current review thus intensively and comprehensively summarized and discussed the mechansims, measurements, determinants, and applications of CPM. First, the neurophysiological and biochemical mechanisms of CPM are summarized. CPM process involves activities from multiple pathways, including (1) spinal-medullary-spinal pathway, with ascending information projecting from the spinal cord toward supraspinal centers, and descending information projecting from the supraspinal brain to dorsal horns neurons; and (2) cortical and subcortical pathways, such as prefrontal cortex and anterior cingulate cortex. The neurotransimitters involved in the biochemical process of CPM include serotonin, opioid, norepinephrine, etc. Second, the traditional psychophysical paradigms of assessing individual CPM efficiency are discussed. The measurement of CPM efficiency is mainly based on evaluating the suppresion of subjective pain perception to the test stimlus, induced by the delivery of the conditioning stimulus, but the approaches are not consistent, characterized as the variations in the modality, intensity, and stimulus site of test and conditioning stimuli. Thus, the standardized approach of evluating CPM efficiency is in demanding for comprhesive comparisions of CPM related studies. With accumulating studies indicating the cortical and subcortical actvities associated with CPM process, we proposed to comprehensively and objectively evaluate individual CPM efficiency, with the combination of psychophysical (e.g., behavioral ratings) and neurophysiological meaures (e.g., electroencephalography and functional magnetic resonance imaging). Third, multi-dimensional factors could influence individual CPM efficiency, including (1) demographical factors, e.g., age, sex, and ethnicity; (2) physiologial factors, e.g., cardiovascular actvities; and (3) psychological factors, e.g., attention, expection, and pain catastrophizing. It suggests that CPM efficiency is multifactorial determinant, and researchers/workers in both basic and clinical fields should systemically and comprehensively consider the various contributing factors to CPM efficiency. Finally, the clinical applications of CPM, both in chronic pain patients and in healthy individuals, are highlighted. The association between chronic pain and CPM dysfucntion/deficts has ever been showed on many types of chronic pain patients, such as fibromyalgia syndrome, temporomandibular disorders, and irritable bowel syndrome, indicating possible applications of CPM in chronic pain treatment. In addition, the CPM efficiency of individual patient, i.e., the function of endogenous pain moduation system for individual patient, could even predict the consumption of morphine, as well the risk of chronic pain development. Besides the applications of CPM on patients, CPM efficiency of healthy populations could even be used as an index of evaluating the health-realted quality of life. In summary, to advance the CPM-related applicaitons in clinical practice, we propose to (1) comprehensively evaluate individual CPM efficiency with the combination of the psychophysical and neurophysiological approaches; and (2) systematically consider the muti-dimensional factors influencing individual CPM efficiency. This is important in both basic and clincial studies, which could not only help us gain insights into the underlying mechanisms of endogeneous pain modualtion, but also provide rational evidence for chronic pain prediction and treatment in clincial practice.