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This review summarizes functional magnetic resonance imaging (fMRI) findings that have informed …

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Background: 'O (Chronic) Pain Miserum'
- Breaking down the barriers: fMRI applications in pain, analgesia and analgesics

Background: 'O (Chronic) Pain Miserum'

At least two major hurdles remain in the treatment of chronic pain. The first is that no objective test for pain currently exists. A blood test, genetic marker or psychophysical measure would greatly improve diagnosis of chronic pain. The second is the lack of an "antibiotic equivalent" (i.e., drugs with high sensitivity and specificity) for the treatment of chronic pain subtypes (e.g., neuropathic pain). Controlled trials of drug efficacy indicate that, on average, the most effective drugs of different classes have similar efficacy (around 30% greater than placebo) across neuropathic conditions [1-3]. Analgesic use is dictated by both efficacy and adverse side effects and side effects can sometimes take precedence over efficacy [4]. A lack of controlled trials for other methods of pain treatment (interventional, psychological, physical therapy) makes it difficult for physicians to evaluate these possible therapies. As a result, chronic pain treatment is difficult, and physicians and patients often resort to using multiple treatments simultaneously or sequentially in the effort to achieve pain relief. Unfortunately, even a combined therapeutic approach frequently offers little benefit (Figure 1).

Recent advances in functional imaging have revolutionized our concept of central process of pain. Indeed, it seems that we are on the verge of using this technology to reach a fundamental new understanding of clinical pain, particularly chronic pain (defined as pain lasting for more than 6 months). Subdivision of chronic pain syndromes into chronic neuropathic pain (e.g., phantom pain, post-herpetic neuralgia), chronic nociceptive pain (e.g., arthritis, migraine), and a group comprising very poorly understood categories of pain (e.g., fibromyalgia, depression-induced pain, or complex regional pain syndrome) has not clarified mechanistic processes. Even classification of chronic pain types based on clinical disease (e.g., cancer pain, diabetic pain) has not proved very helpful in understanding the mechanisms underlying chronic pain. Recently a mechanistic approach to defining pain has been suggested in which specific pain phenotypes such as shooting pain, burning pain, and allodynia can be applied across pain types such as neuropathic pain. [5]. However, this approach is based primarily on an understanding of peripheral nerve and spinal cord processing. Functional imaging has already redefined chronic pain as a degenerative disease, and has shed some light on complex diseases such as fibromyalgia [6]. Since brain responses are the final common pathway in behavioral responses to pain (unconscious and conscious), we believe that the application of functional imaging will allow us to categorize pain conditions in an objective manner and to better understand the underlying circuitry and identify targets for a new generation of analgesics [7,8].

fMRI measures neural activity by an indirect evaluation of changes in blood flow in capillary beds [9]. A number of approaches including block design [10], event-related [11], and percept-related. [12] paradigms, have been applied to fMRI studies of physiological, clinical and pharmacological aspects of pain and analgesia. Application of baseline measures of spontaneous pain have allowed the "basal state" to be evaluated.) [13]. Issues pertaining to the validity of fMRI in pain and analgesic measures have been presented elsewhere [14].

"To consider only the sensory features of pain, and ignore its motivational and affective properties, is to look at only part of the problem, not even the most important part at that." This statement of Melzack and Casey's [15] was an early recognition of these aspects of pain, but their importance is now widely accepted. The ability to use fMRI to image the whole brain at the same time and to use powerful algorithms to segregate functional circuits allows us to begin to elucidate the CNS processes underlying affective and motivational components of pain. It also allows a broader window to observe potential CNS sites of drug action. Our understanding of 'difficult' disease states (e.g., fibromyalgia or depression-related pain), the placebo response, emotional responses (e.g., empathy), and acupuncture will clearly be influenced by new insights into how emotional circuitry in the brain functions in pain states and in responses to analgesics. [16]. In this paper, we review the contribution of fMRI to the understanding of acute and chronic pain, its use in surrogate models and for evaluation of endogenous pain systems including the placebo response, and its potential use as an objective measure of analgesic efficacy. The approach we have taken to summarize the new advances has been to provide an overview for each domain (e.g., Acute and Chronic pain, Endogenous Systems etc.) and summary tables that focus on specific areas within each domain (e.g., Chronic pain: Neuropathic, Fibromyalgia etc.). Studies listed are predominantly from peer-reviewed journals (Data Sources: Medline) or data from our own lab presented at Society for Neuroscience and/or in press. We attempted to include primary examples on specific entities of CNS processing as defined with fMRI that are related to pain, analgesia and analgesics.

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