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).

Figure 1
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The problem with chronic pain. Therapy for acute pain (e.g., acute inflammation, trauma, post-surgical pain) is overall excellent. However, in chronic pain (e.g., neuropathic pain, fibromyalgia, complex regional pain syndrome), therapy is poor. This group thus falls into a zone (circles) of "therapeutic failure" or "therapeutic impasse" where multiple therapies are tried with overall little success. Functional imaging appears poised to open up new approaches to the understanding of chronic pain conditions. An improved basic understanding of the mechanisms underlying chronic pain is likely to suggest new avenues for the development of novel pharmacotherapies.

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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.

Advancing our Understanding of CNS Mechanisms in Acute and Chronic Pain through fMRI

fMRI of Physiological Pain – a new understanding of brain regionsinvolved in pain processing in humans

Much of the work in fMRI of pain has utilized thermal stimuli (contact peltier thermodes or laser) to activate pain circuits. Other types of stimuli, including electrical and mechanical (pressure) have not been as extensively used either in the intact system or where sensitization has been experimentally induced (see Table 3). The accumulation of data has begun to identify brain regions involved in pain processing – from peripheral ganglia to central limbic and brainstem structures previously only implicated in animal studies in the preclinical literature (see Table 1).

Table 3 Examples fMRI Studies of Surrogate Models of Pain
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Table 1 Examples of Contributions by fMRI on the understanding Brain Regions activated by Acute Pain
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Some of these regions are part of well-defined pain circuits (e.g., PAG, parabrachial nuclei) while for others such as the nucleus accumbens, their specific role in pain processing is not well understood [17, 18]. Studies have reported specificity of somatotopic organization of structures outside of the primary somatosensory cortex involved in pain processing in humans; these such as the insula [19] and the trigeminal system [14, 20]. Indeed, the results of human imaging help focus attention on specific regions, including the nucleus accumbens (involved in emotional salience), the insula (involved in specific interpretation of noxious stimuli) or the amygdala (involved in fear), opening new vistas for understanding how the human brain evaluates pain. The ability to evaluate activity and organize active regions into neural circuits that subserve specific pain/analgesia functions (i.e., sensory, emotional, autonomic, endogenous analgesic circuits) is a step forward. A number of studies have already begun this task including segregation of function within a structure (e.g., PAG [17] and NAc [18]), defining analgesia as a rewarding process [21], and functional differentiation of activation sites within a particular brain region (e.g., cognitive and affective regions within the anterior cingulate [17]).

What is needed now is to further evaluate these brain areas, some of whose role is newly defined in pain processing in humans, at a functional level. Several new fMRI approaches will aid this effort including techniques that allow definition of large scale systems organization [22]; techniques that define circuits/functional connectivity [23]; and automated parcellation of brain structures [24, 25] including the thalamus [26]. Imaging studies have not only unveiled new regions involved in pain processing, but have also contributed new insights into the functioning of these regions in experimental pain. For example, the hippocampus, classically associated with memory, has been shown to be involved in pain-induced anxiety [27–29].

fMRI of Chronic Pain

Imaging clinical conditions is fraught with issues that make it more challenging, including the fact that it is difficult to assemble a cohort with similar symptoms, duration of disease, medication history, age distribution, etc. Among clinical conditions, chronic pain has a particularly wide spectrum of patient presentations and medical histories. However, studies have begun to evaluate CNS changes that occur in patients with chronic pain (see review by Apkarian and colleagues [30]), including those with neuropathic pain, fibromyalgia, complex regional pain syndrome and visceral pain (Table 2).

Table 2 Examples of Contributions of fMRI to the understanding of CNS circuitry underlying Chronic Pain
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A number of important issues are emerging in the evaluation of chronic pain conditions as fMRI and associated imaging technologies become more sophisticated. Chronic pain produces changes that become manifest as alterations in the central nervous system. One may term this "centralization of hyperalgesia" or "centralization of pain". This has been evaluated across diseases including fibromyalgia [6], chronic back pain [31], and irritable bowel syndrome [32]. During functional imaging of fibromyalgia and chronic back pain, enhanced responses to thermal or mechanical stimuli that are applied heterotopically (i.e., away from the actual location of the pain) are present in a number of CNS regions, including non-sensory regions. Differences in specific responses to brush, heat and cold in affected vs. intact regions in patients with neuropathic pain have also been reported [33]. One feature that seems to be of in common with chronic pain patients is significantly greater frontal lobe activation in chronic pain sufferers [30]. This feature, suggests that in chronic pain CNS activity in regions involved in cognitive processing differs between acute and chronic pain. These insights are further complicated by the new and revolutionary recognition that, in chronic pain, neuronal loss occurs in significant pain pathways including the thalamus and the lateral prefrontal cortex [34]. The role of this neurodegeneration in producing either the altered CNS responses or the pain state is not understood.

Maladaptative changes in non-sensory circuits may contribute to the psychological states, including depression, anxiety and amotivation that are often seen in these patients. Thus the study of specific brain regions such as the nucleus accumbens (involved in probability assessments and reward evaluation), the amygdala (involved in orientating to and the memory of motivationally salient stimuli), the hippocampus (involved in evaluating the expectancy of an unknown condition), the prefrontal cortex (involved in cognitive and planning functions around emotional stimuli or regarding rewarding or aversive outcomes) and the anterior cingulated cortex (involved in the rank ordering of the value or salience of the stimulus) may provide new insights into brain functioning in these co-morbid conditions. Such insights should provide immediate benefits to the understanding of the calcitrant nature of chronic pain to therapeutic interventions.

Our increased recognition that multiple neural systems are involved in pain processing and affect pain perception (reward/aversion circuitry, the role of anticipation, neural systems interpreting different pain types albeit at the same intensity, opponent systems and drug effects) suggests that multiple neural circuitries are likely affected in chronic pain. Results published thus far indicate that: (1) Pain intensity is probably not a good marker for changes in chronic pain state. Neural imaging may be able to define a correlation between CNS activation and patient answers to a simple subjective questionnaire that assesses emotional and other components of pain and suffering; (2) Neural systems interpreting components of the pain response (e.g., emotional, empathy, anticipation etc.) are clearly complex, and we still have no understanding of how these may change in the chronic pain condition; and (3) Standards will need to be applied across imaging facilities in order to interpret and compare data across studies.

fMRI of Human Surrogate Pain Models

Defining valid surrogate models has been a problem in both animal and human models of pain [35–37]. In human studies, mechanical (heat) or chemical (capsaicin) sensitization of skin and testing in primary and secondary regions affected has been used as a surrogate for neuropathic pain (hyperalgesia/allodynia to thermal and mechanical stimuli) [38]. Recently fMRI has been used to evaluate the capsaicin – induced hyperalgesia model (see Table 3). While many of these studies report increased activation in a number of brain regions, some of the more recent studies begin to define the utility of fMRI in dissecting mechanistic changes or insights using this model [39–41]. These studies demonstrate differences in brain activation in response to stimuli of equivalent pain intensity delivered in sensitized vs. non-sensitized state, providing further evidence that pain intensity by itself is probably not a useful measure of the status of the underlying pain processing circuitry [41]. An alternate explanation may be that there are mechanistic differences between these two states. Changes in perceived pain intensity may reflect acute changes in CNS sensory pathways but may not correlate with changes in CNS emotional pathways which may be relevant to an individuals' overall response to pain and may predict future pain conditions. Eventually, fMRI should allow the direct comparison of activation in specific CNS regions in experimental models with the activation seen in patients with neuropathic pain. Comparing such objective measures should allow us to determine where the model differs from the disease and to assess the validity of such models for evaluating potential therapies.

fMRI studies of Endogenous Analgesia

Endogenous modulatory networks can either facilitate or inhibit pain[42, 43]. Endogenous analgesia refers to systems that produce the latter. These systems involve a network that includes higher cortical (e.g., anterior cingulate cortex) and subcortical regions (e.g., the amygdala, hypothalamus) that project to brainstem nuclei (periaqueductal gray and raphe nuclei) that send projections to the dorsal horn [44] These systems can be modulated by a number of factors including stress, pain and the placebo response [42].

A number of studies have used fMRI to investigate endogenous modulation of pain (Table 4) and map circuits involved in CNS systems that can alter decrease or increase pain [45–47]. Most of these studies involved attention or distraction to modulate circuits. In addition, closely linked with this are studies of placebo response, evaluation of the effects of attention and expectancy, of empathetic reactions to pain in others, to producing "trickery" of the brain by sensory inputs [48].

Table 4 Examples of Contributions of fMRI on Endogenous Mechanisms of Pain or Analgesia
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Perhaps of greatest importance are studies of the placebo effect since there has been a significant literature in this domain from psychophysical studies [49, 50]. A neurobiology and neurocircuitry were predicted for the placebo effect based on its effects on analgesia. [51]. Indeed the general circuitry of the placebo response can be applied to non-painful stimuli. These and other studies have enhanced our knowledge of the interaction of physiological pain circuits and cognitive/emotional circuits [52]. The use of imaging has now clearly established how some of these endogenous systems operate. This understanding coupled with an objective method of evaluating placebo should provide novel insights into drug development as well as the treatment of patients with acute and chronic pain.

Complementary with fMRI studies on placebo, the use of fMRI has identified neural systems involved in anxiety and fear related to pain. These two reactions to pain are important both from a neuroscience aspect. [16] as well as from practical applications of treating patients. While fear and anxiety have been considered to have different effects on neural processing [53], recent fMRI studies have begun to explore this issue [54].

The innate nature of the pain experience is clearly indicated by studies showing that activations in non-sensory CNS systems in an observer experiencing empathetic pain, are similar to those produced in a subject by noxious stimuli. The study of endogenous analgesia highlights the opponent systems operating in pain. In addition, fMRI studies reveal that in addition to the sensory pathways activated in endogenous analgesia and pain processing, reward/aversion circuitry is activated, with reward related to pain relief and aversion related to pain. [21]. The balance between these opponent systems may be crucial in determining the overall sensory and emotional experience of pain in chronic pain states.

fMRI has also been applied to exploring the neurobiology of acupuncture, which is believed to activate endogenous analgesic mechanisms [55]. Such studies have predominantly been in healthy subjects using experimental pain. The evidence for the benefit of acupuncture for clinical studies has been mixed. For example, recent studies in migraine patients has indicated that acupuncture may be no more effective than sham acupuncture in reducing migraine headaches, although both are more effective than no intervention. Such studies need to be repeated, but raise questions as to how acupuncture works (for example, through activation of diffuse noxious inhibitory controls or activation of endogenous systems through expectancy etc.) [56]. In carefully devised studies, defining brain circuits involved in expectancy, treatment etc. may help provide a more objective evaluation of such interventions.

fMRI Studies of Analgesics

fMRI is also being applied to the evaluation of analgesics (pharmacological MRI or phMRI). [57]. Examples are provided in Table 5.

Table 5 Examples of Contributions of fMRI on Analgesics
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Analgesic effects on brain systems or neural circuits (stimulus independent) – Many analgesics have direct CNS effects, and very little is known about how they act on the human brain. Such studies are most often performed in healthy volunteers. Here the direct effect of administration of a drug is observed without any stimulus paradigm. These types of studies allow for the interrogation of effects that may not be obvious (e.g., subcortical, subconscious), for integration of how drugs may have a role on intact brain systems that still may be the case in the chronic pain state, and for the evaluation of potential side effects of drugs. Our naloxone and morphine studies (see Table 4; [58, 59]) have taken this approach and indicate the ability to evaluate direct drug effects even when there are no obvious psychophysical effects (naloxone) or well-described side effect profiles (morphine) that can be evaluated based on circuit activation (e.g., reward, sedation or analgesic circuits). [59]. The ability to define specific differences across classes of drugs (e.g., antidepressants, membrane stabilizers, opioids) may not only help focus on common areas of potential mechanisms but also provide information within different drug classes (e.g., antidepressants – tricyclics vs. serotonin norepinehprine reuptake inhibitors). Advances in this domain should lead to use of standardized fMRI trials for early phase evaluation of pharmacotherapies for pain [60].

Analgesic effects on acute or chronic pain (stimulus-dependent) – In this group, the effect of the drug is evaluated in subjects usually following an applied painful stimulus. A few examples of this type of approach include the studies of cyclooxygenase (cox) inhibitors [61] and amitriptyline [62] in chronic pain conditions and the effects of drugs on capsaicin-induced hyperalgesia (see Table 5). These approaches show that pharmacological evaluation of the CNS effects of drugs is possible, suggesting that fMRI can be used for objective assessments of drug efficacy; until now, all assessments of analgesic efficacy relied on subjective psychophysical measures.

Conclusion

A revolution in the application of a relatively new technology, fMRI, to the field of pain and analgesia is upon us. Within the next half decade, we should begin to see direct benefits in the clinical setting that could range from (a) use of fMRI to evaluate/diagnose a pain condition; (b) use of fMRI to evaluate drug efficacy in responders vs. non-responders; (c) use of fMRI to evaluate novel drug efficacy (the latter will be driven predominantly by the pharmaceutical industry) and (d) use of fMRI to provide new insights into the mechanisms of endogenous 'pain systems'. We believe there is good reason to expect that the contribution of this technology together with advances in other neurosciences will help transition the state of current pain therapy from 'o me miserum!' ('o woe is me!') to more optimistic states for both patient and clinician 'semper aliqud novii' ('always something new' .... and better/useful). We believe there is good reason to expect that the contribution of this technology together with advances in other neurosciences will significantly advance therapies for chronic pain and alleviate physical and emotional suffering for the many individuals living with this disease.