Amanda Wray -Understanding Chronic Pain and Fibromyalgia: A Review of Recent Discoveries by Robert M. Bennett MD, FRCP Professor of Medicine, Oregon Health Sciences University Fibromyalgia tends to be treated rather dismissively, sometimes with cynical overtones. When I trained in London some 30 years ago, this diagnosis was never mentioned, even though I trained with one of the foremost rheumatologists in the world at the time. In the United States fibromyalgia has become a semi-respectable diagnosis within the last 10 years, but even so it has some critics. The problem for doctors is that fibromyalgia is not a problem that can be understood according to the classic medical model. This is the model that is used in all medical training. It is based on the correlation of specific tissue pathology with distinctive symptoms (e.g. tuberculosis of the lung causing a chronic cough). Elimination of the causative agent (e.g. the tubercule bacillus) cures the disease. This model has led to the most major advances in medicine that we benefit from today. I have seen over 5,000 fibromyalgia patients over the past 20 years; most want to be reassured that their symptoms are the product of a "real disease" rather than figments of a fertile imagination--commonly ascribed to the psychological diagnosis such as somatization, hypochondriasis, or depression. The good news is that contemporary research is hot on the track of unraveling the changes that occur within the nervous system of fibromyalgia patients. The basic message is that fibromyalgia cannot be considered a primarily psychological disorder, but as in many chronic conditions, psychological factors may play a role in who becomes disabled and may even up-regulate the central nervous system changes that are the root cause of the problem. What is the problem? The problem is: disordered sensory processing. I will try to convey to you what we mean by "disordered sensory processing." Even a superficial understanding of this topic will change the way you think about the fibromyalgia problem. Furthermore, recent advances that have been made at the molecular level hold out the promise of more effective treatment for fibromyalgia pain. What is Fibromyalgia? Fibromyalgia is a chronic pain state in which the nerve stimuli causing pain originates mainly in the muscle. Hence the increased pain on movement and the aggravation of fibromyalgia by strenuous exertion. Pain is a universal experience that serves the vital function of triggering avoidance. A few unfortunate individuals have a congenital absence of pain sensation; they do not fare well due to repeated bodily insults that go unnoticed. As a physician I see patients with an acquired deficiency in the pain sensation (e.g. diabetic neuropathy or neurosyphilis) who develop a severe destructive arthritis--a result of repeated minor joint injuries that are overlooked. Thus pain sensation is a necessary part of being human. Pain sensation is a fact of life. Even the primitive amoeba takes avoiding action in the face of adverse events. In such primitive life forms, pain avoidance is purely reflex action, as they do not have the complexity of a highly developed brain to feel pain in the sense that humans do: (1)The unconscious reflex avoidance reaction that is so rapid that it occurs before the actual awareness of the pain sensation (as in all life forms), (2) the actual experience of the pain sensation (that can only occur in highly complex organisms). This is an important point, as it implies that different parts of the brain are involved in these two consequences of the pain reaction. Over the last few years a number of important research discoveries have started to clarify the enigma of chronic pain. Many of these new findings have a special relevance to the chronic pain of fibromyalgia. The cardinal symptom of FM is widespread body pain. The cardinal finding is the presence of focal areas of hyperalgesia, the tender points. Tender points imply that the patient has a local area of reduced pain threshold, suggesting a peripheral pathology. In general, tender points occur at muscle tendon junctions, a site where mechanical forces are most likely to cause micro-injuries. Many--but not all--FM patients have tender skin and an overall reduction in pain threshold. These latter observations suggest that some FM patients have a generalized pain amplification state. There has been a recent plethora of experimental studies apposite to the pathophysiological basis of both the peripheral and central aspects of pain. The Pathophysiological Basis for Chronic Pain The International Association For the Study of Pain (ASP) defines pain as follows: "Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage." This definition explicitly affirms that pain has both a sensory and an affective-evaluative component, and furthermore acknowledges that it may occur in the absence of obvious visceral or peripheral pathology. To fully understand chronic pain, one must integrate the sensory and affective/evaluative elements of the pain experience. It is equally misguided to focus on the psychological aspects of pain, as it is to address only the sensory component and ignore the affective dimensions. However, for the sake of clarity, each of these two constitutive elements will be considered separately. The Sensory Component Pain is generally envisaged as a cascade of impulses that originates from nocioceptors in somatic or visceral tissues. The impulses travel in peripheral nerves with a first synapse in the dorsal horn and a second synapse in the thalamus, and end up in the cerebral cortex and other supraspinal structures. This results in an experience of pain and the activation of reflex and later reflective behaviors. These reflex and reflective behaviors are aimed at eliminating further pain. The expectation is that this nocioceptor driven pain will be successfully abolished, allowing healing and a return to a pain-free state. The problem with chronic pain is that the linear relationship between nocioception and pain experience is inappropriate or even absent, and the expected recovery does not occur. It is a common misconception to view the nervous system as being "hard-wired"; that is, stimulation of a nerve ending (say a needle prick) always produces the same behavioral and affective response. This concept implies that the same intensity of pain stimulus will always elicit the same degree of nerve stimulation and hence the same subjective experience of pain. It is now understood that the concept is wrong. Some 30 years ago, Melzeck and Wall proposed that pain is a complex integration of noxious stimuli, affective traits, and cognitive factors. In other words, the emotional aspects of having a chronic pain state and one's rationalization of the problem may both influence the final experience of pain. Mendell and Wall provided the first experimental evidence that the nervous system was not hard-wired in 1965. They noted that a repetitive stimulation of a peripheral nerve, at sufficient intensity to activate C-fibers, resulted a progressive build-up of the amplitude of the electrical response recorded in the second order dorsal horn neurons. If the system had been hard-wired, each stimulus would have elicited the same response in the second order neuron. They termed this phenomenon "wind-up." It is now appreciated that the phenomenon of wind-up is crucial to understanding the problem of chronic pain via the mechanism of "central sensitization." Central sensitization refers to an increased activation of second order neurons in the spinal cord, resulting from injury or inflammation-induced activation of peripheral nocioceptors. Sensory input from muscle, as opposed to skin, is a much more potent effector of central sensitization. This may be the clue to the role of muscle pain in the total spectrum of fibromyalgia. A common example of central sensitization is post-herpetic neuralgia. Previous injury to a peripheral nerve leads to an amplification of both nocioceptive and non-nocioceptive impulses. The mechanism responsible for the abnormal perception of non-nocioceptive impulses in post-herpetic neuralgia is an increased excitation of second order nocioceptive neurons in the dorsal horn of the spinal cord. A special example of central pain occurs when there is pathology within the central nervous system. This occurs in a thalamic stroke--severe unilateral pain, often accompanied by strong emotions, that occurs in the absence of any nocioceptive input. There are two forms of second order spinal neurons involved in central sensitization. (1) Nocioceptive--specific neurons--respond only to nocioceptive stimuli, and (2) Wide dynamic range neurons--respond to both nocioceptive and non-nocioceptive afferent stimuli. Both may be sensitized by nocioceptive stimuli leading to central senitization but wide-dynamic range neurons are generally more intensely sensitized than nocioceptive-specific neurons. Nocioceptive and non-nocioceptive peripheral nerves often converge onto the same wide dynamic range neuron (see figure). Once sensitized by ongoing nocioceptive impulses from peripheral nerves, wide-dynamic range neurons will respond to non-nocioceptive stimuli just as intensely as they did prior to sensitization. This results in sensitizations like a light touch to be experienced as pain (i.e. allodynia). Sensitization of wide-dynamic range neurons by prior pain stimuli provides the pathophysiological foundation for nonnocioceptive pain. There is emerging evidence that afferent activity from Golgi tendon organs and muscle spindles can be converted into pain signals under the influence of central sensitization. For instance, some patients with strokes and spinal cord injuries develop severe pain on movement. Benc has proposed the term "proprioceptive allodynia" to describe this phenomenon. He describes such individuals as "while not experiencing pain at rest, they develop excruciating burning and tingling, often difficult to describe, that appear only when trying to hold an object, move a limb, stand or walk." Thus everyday muscle activity may cause pain and impair function in some individuals with central sensitization. At a physiological level, pain on movement implies that proprioceptive afferents are projecting onto second order wide-dynamic-range spinal neurons that have been sensitized by previous nocioceptive activity. Thus the central nervous system of subjects who have ongoing pain (e.g. arthritis) or have had previous pain experiences (e.g. post injury pain) may be permanently altered due to changes that can now be understood at the physiological molecular and structural levels. At a clinical level this is seen as persistent pain in survivors of serious illness who experienced high levels of pain during hospitalization, persistent pain after breast surgery, or the occurrence of fibromyalgia after automobile accidents. The reason why the phenomenon of central sensitization only occurs in a minority of individuals is not currently known. At a molecular level, there are many studies demonstrating the important role of excitatory amino acids such as glutamate and neuropeptides such as substance P in the generation of central sensitization. Substance P and CRGP are important neurotransmitters in lowering the threshold of synaptic excitability, which permits the unmasking of normally silent interspinal synapses and the sensitization of second order spinal neurons. Substance P, unlike the excitatory amino acids, can diffuse long distances in the spinal cord and sensitize dorsal horn neurons in spinal segments both above and below the input segment--with resulting pain signal generation from non-nocioceptive afferent activity. Clinically this will lead to an expansion of receptive fields; e.g. the spread of pain to uninjured areas after an automobile accident. The Psychological Component It was seen in the preceding section that chronic pain could occur in the absence of ongoing tissue damage--this is an example of the sensory component of pain. It was also noted that one component of pain is a reflex avoidance behavior that can occur before the conscious appreciation of pain. In terms of brain physiology this implies that more primitive parts of the brain contain several discrete nuclei (e.g. the thalamus, cingulate gyrus, hippocampus, amygdyala, and locus ceruleus) that interact to form a functional unit called the limbic system. This is the part of the brain that subserves many reflex phenomena, including the association of sensory input with specific mood states (e.g. pleasure, fear, aversion etc.). These facts form the physiological basis for considering the emotional aspect of pain. Interestingly, the electrical stimulation of the brain during neurosurgical procedure does not induce pain sensations in pain-free subjects. However, in past pain patients it often reawakens previous pain experiences. It is surmised that such stimulation re-activates cortical and subcortical pain circuits that were previously dormant. It is not known whether there is a single cortical structure that subserves pain memory. Currently it appears that different cortical and subcortical structures are involved in the pain experience. For instance, removal of the somatosensory cortex does not abolish chronic pain, but excision of lesions of the anterior cingulated cortex reduces the unpleasantness of pain. The anterior cingulated cortex is involved in the integration of affect cognition and motor response aspects of pain and exhibit increased activity on PET studies of pain patients. Other structures involved in cortical pain processing include the prefrontal cortex (activation of avoidance strategies, diversion of attention and motor inhibition); the amygdala (emotional significance and activation of hypervigilance); and the locus ceruleus (activation of the "fight or flight" response). All these structures are linked to the medial thalamus, whereas the lateral thalamus is linked to the somatosensory cortex (pain localization). One example of limbic system activation is the hypervigilance that accompanies many chronic pain states, including fibromyalgia. The emotional component of pain is multifactorial and includes past experiences, genetic factors, generals state of health, the presence of depression and other psychological diagnosis, coping mechanisms, and beliefs and fears surrounding the pain diagnosis. Importantly, thoughts as well as other sensations can influence the sensory pain input to consciousness as well as the emotional coloring of the pain sensation. The term given for this modulation of pain impulses is the "gate control theory of pain." Thus thoughts (beliefs, fears, depression, anxiety, anger, helplessness, etc.), as well as peripherally generated sensations, can both dampen or amplify pain. Indeed, in many chronic pain conditions (that lack of any effective therapy for the sensory/pain component), a reduction of pain and the resulting suffering can only be affected by modulating the psychological aspects of pain. As the psychological contribution to pain varies enormously from patient to patient, this approach has to be individualized. However, there are some general principles that are worth noting. There are important consequences of having pain that will not go away (as is the expected experience for most pain in most people). The unsettling realization that the problem may well be life-long generates a varied mix of emotions and behaviors that are often counterproductive to coping with a chronic problem. Many of these changes (which are partly reflex in origin) would be appropriate for dealing with acute self-healing pain events, but become a liability when dealing with chronic pain. The end result of chronic pain is often depressive illness, marital discord, vocational difficulties, chemical dependency, social withdrawal, sleep disorders, increasing fatigue, inappropriate beliefs, and a radical alteration in their previous personality. Varying degrees of functional disability are a common accompaniment of chronic pain states. The reasons for dysfunction are multiple and vary from individual to individual. Pain often monopolizes attention (causing lack of focus on the task at hand). It is usually associated with poor sleep (causing emotional fatigue). Movements may aggravate pain (causing a reluctance to engage in activity). Fear of activity often leads to deconditioning (which predisposes to muscle and tendon injuries and reduced stamina). Pain causes stress, which may result in anxiety, depression, and inappropriate behavior (causing disability due to secondary psychological distress). The modern era of psychological imaging is providing an important new framework for understanding these "emotional" responses.