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htm APS Bulletin Volume 11, Number 1, March/April 2001 Research Update

Richard Gracely, PhD, Department Editor Dyspnea and Pain: Similarities and Contrasts Between Two Very Unpleasant Sensations Robert B. Banzett, PhD; Shakeeb H. Moosavi, PhD Why compare pain and dyspnea? There are few, if any, more unpleasant and frightening experiences than feeling short of breath without any recourse. The prevalence of this symptom is underappreciated; dyspnea (shortness of breath) is actually as common as pain in serious disease. Half of seriously ill patients admitted to tertiary care hospitals report pain, an equal number report dyspnea, and these two symptoms alone account for four fifths of the burden of physical symptoms that were moderately severe or severe (nausea accounting for the remainder) (Desbiens, Mueller-Rizner, Connors, Wenger, Lynn, & Support Investigators, 1999). In the final stages of terminal illness, the severity and frequency of dyspnea increase while pain decreases (Mercadante, Casuccio, & Fulfaro, 2000). Many patients suffer from both of these debilitating symptoms; many diseases such as heart disease, terminal cancer, spontaneous pneumothorax, and amyotrophic lateral sclerosis cause pain and dyspnea. Despite the high prevalence of simultaneous pain and dyspnea in patients, there is only one study of the interaction between the perception of pain and the perception of dyspnea. This study showed that perception of dyspnea was slightly increased by ischemic tourniquet pain, whereas pain was reduced by simultaneous dyspnea (Nishino, Shimoyama, Ide, & Isono, 1999). The distinctly different sensations of pain and dyspnea share important characteristics. Dyspnea and pain (as well as thirst, nausea, and hunger) alert the conscious brain to a disturbed physiological state. Such perceptions strongly motivate adaptive behaviors in situations that threaten homeostasis or situations that require action more complex than simple reflexes. The perception of inadequate breathing motivates adaptive behaviors that ensure adequate air supply. For instance, a strong perception of a need to breathe causes diving animals to surface and causes all animals to struggle to remove external obstruction to air passages; perception of shortness of breath enables animals to limit sustained running speed to avoid cardiopulmonary collapse. There is a strong analogy to pain, which often requires behavioral responses more complicated than a withdrawal reflex (e.g., adjusting gait to minimize pain during required movement). Pain and dyspnea motivate patients to seek treatment for serious disease. As in several pain syndromes, a large number of general medical patients experience dyspnea with no obvious organic cause, leading to unnecessary suffering and costly use of medical resources to rule out other possibilities (Smoller, Pollack, Otto, Rosenbaum, & Kradin, 1996). The state of knowledge in the field of pain and the state of the art in pain treatment are considerably more advanced than knowledge and treatment of dyspnea (Dudgeon & Rosenthal, 1996). Our

laboratory has begun to apply experimental approaches developed in the study of pain to the study of dyspnea. We have found that the conceptual framework developed for pain is useful in our attempts to understand dyspnea; pain scientists may likewise profit from comparison of pain to another cardinal form of discomfort. A primer on dyspnea The word dyspnea subsumes a variety of unpleasant respiratory sensations described by terms such as chest tightness, excessive breathing effort, shortness of breath, and air hunger (Howell, 1970). Air hunger is described as not getting enough air, or as an uncomfortable urge to breathe and is like the perception at the end of a long breath hold (Banzett, et al., 1990; Banzett, Lansing, Evans, & Shea, 1996). Tightness is an uncomfortable symptom localized to the chest, usually reported by asthmatics (Simon et al., 1990). A perception of the effort or work of breathing is evoked when the work of breathing is increased by high ventilation or external loads; respiratory effort or work can be uncomfortable if excessive or prolonged (Killian, Gandevia, Summers, & Campbell, 1984; Lansing, Im, Thwing, Legedza, & Banzett, 2000). Air hunger probably underlies or accompanies most perceptions of dyspnea in the clinical setting. Like pain, air hunger is distressing. Subjects exposed to severe air hunger under laboratory conditions report a sense of impending death (Hill & Flack, 1908; Banzett et al., 1990) and sometimes volunteer that they would prefer pain to air hunger (no formal comparison has been made). The prevailing level of spontaneous ventilation is largely determined by the level of arterial carbon dioxide. When arterial carbon dioxide concentration increases even slightly, or arterial oxygen concentration decreases substantially, motor centers in the brainstem produce a reflex increase in motor drive to respiratory muscles (often termed ventilatory drive). This increased motor drive normally increases breathing enough to restore homeostasis by increasing the transport of oxygen into, and carbon dioxide out of, the lungs. Mechanoreceptors in the lungs and chest wall immediately report the achieved pulmonary ventilation via vagal and somatic afferents, chemoreceptors later report the reestablishment of acceptable blood oxygen and carbon dioxide concentrations. Air hunger arises when the level of ventilatory drive rises, especially if mechanoreceptor information from the lungs indicates that breathing is inadequate. Thus, an increase in pulmonary ventilation relieves air hunger, a decrease in pulmonary ventilation increases air hunger at a given ventilatory drive (e.g., achieved in the laboratory by fixing arterial carbon dioxide partial pressure and oxygen partial pressure) (Hill & Flack, 1908; Manning et al., 1992). The sensation of tightness or chest constriction occurs during episodes of bronchoconstriction and is a symptom fairly specific to asthma; tightness may occur in isolation or combined with other dyspneic sensations. Tightness may arise from stimulation of pulmonary afferents (Binks, Moosavi, Banzett, & Schwartzstein, 2000). A sense of respiratory work and effort is present in several clinical conditions such as asthma, chronic obstructive disease (emphysema), and neuromuscular diseases that impair respiratory muscles. This sensation also can be evoked by the imposition of external loads either in the laboratory or during the use of occupational breathing devices. Perception of work and effort probably arise through some combination of respiratory muscle afferents and perceived central neural motor command (Gandevia, Killian, & Campbell, 1981; Moosavi et al., 2000). Similarities and differences in the study of pain and dyspnea

Like pain, the sensory and affective experience of dyspnea is complex. Over the years, considerable research effort has gone into the development of standardized instruments that can convey meaningful information about pain sensations. One of the most important contributions has been the recognition of the multidimensionality of pain. Pain research has been greatly aided by the development of measurement instruments such as the McGill Pain Questionnaire (Melzack, 1975) and verbal descriptor scales of sensory intensity and unpleasantness (Gracely, McGrath, & Dubner, 1978). Although several studies have shown that the breathing sensations vary systematically with various respiratory stimuli and clinical conditions (Elliott et al., 1991; Simon et al., 1989; Simon et al., 1990), standard instruments that formalize the procedure for obtaining verbal reports of respiratory sensation have yet to achieve widespread acceptance and validation. There has been only one published paper attempting to quantify multiple dimensions of dyspnea (Wilson & Jones, 1991). Also, like pain, the language available to a study participant to describe dyspnea is much less precise than that for vision or hearing. The language difficulty may result from the lack of a common external standard on which we can agreejust as in the common expression your pain is your pain, your dyspnea is your dyspnea. However, differences in the variety and extent in which pain and dyspnea are experienced in early life may influence the ability to recognize and describe them. Because, unlike pain, inescapable and prolonged episodes of dyspnea are seldom experienced until one contracts diseases characteristic of later life, this could explain why language is less developed for dyspnea. In addition, unlike most pain, the sense of air hunger does not have a clear location in the body (although some study participants localize it to the chest). This is analogous to hunger for food, which is sometimes, but not always, localized to the stomach. Another, more practical, problem in the study of dyspnea is its characteristically slow onset and offset, which makes methods depending on precise temporal triggering impractical (e.g., event-related potentials) and also limits the number of repeated trials that can be delivered to a study participant in one session. Commonality of central neural processing of pain and dyspnea The afferent mechanisms responsible for dyspnea are probably even more complicated than for pain. Dyspnea involves several distinct classes of sensation (e.g., air hunger, tightness, and work). These in turn are subserved by different classes of somatic and visceral afferents from the chemoreceptors, the lungs, and the respiratory muscles, and probably by corollary discharge from respiratory motor centers in the cortex and brainstem (Banzett & Lansing, 1996). Furthermore, the sense of air hunger involves comparison of the need for air with afferent information about the supply of air. Thus, no linear pathway from receptor to brain can be identified; we cannot stimulate primary afferents in reduced preparations and infer that the stimulation would have resulted in dyspnea in the intact animal. Pain and dyspnea require an array of central neural mechanisms subserving arousal, detection, perceptual analysis, motivation, and preparation of motor response. Surely some of the neural mechanisms are unique to each sensation, but it is possible that neural structures subserving distress and discomfort in general will be shared. Positron emission tomography (PET) and functional magnetic resonance imaging techniques have been widely used to study perception of pain. Since the first PET images of the human cortical representation of pain published a decade ago (Jones, Brown, Friston, Qi, & Frackowiak, 1991; Talbot et al., 1991), there have been scores of published studies of cerebral activation in pain. These methods have been applied to dyspnea only recently. In the first study of its kind, we mapped the cortical activations associated with dyspnea using PET (Banzett et al., 2000). We found a strong activation of the anterior insular cortex when normal participants experienced severe air hunger. More recent studies have confirmed and

extended this finding (Evans, Banzett, Mckay, Frackowiak, & Corfield, 2000; Peiffer, Poline, Thivard, Aubier, & Samson, in press). Although functional similarities between breathing and pain have been recognized for some time, this is the first functional anatomic evidence closely relating pain to dyspnea. Activation of the anterior insula, a limbic structure, is almost always found in PET studies of human pain (Banzett et al., 2000; Treede, Kenshalo, Gracely, & Jones, 1999). Activation in the region of anterior insula also has been seen in humans experiencing nausea (Miller, Rowley, Roberts, & Kucharczyk, 1996), disagreeable taste and odor (Kettenmann, Hummel, Stefan, & Kobal, 1997; Kinomura et al., 1994), and other aversive experiences (Buchel, Morris, Dolan, & Friston, 1998; Phillips et al., 1997). It has been suggested that the anterior insula is an internal alarm center, alerting the individual to potentially distressing interoceptive stimuliinvesting them with negative emotional significance (Reiman et al., 1997). During air hunger we also found weaker foci of neuronal activation. Foci in the midline supplementary motor area and in the frontal opercula have been associated with motor planning; analogous activations have been seen during experimental itch (Hsieh et al., 1994) and during cutaneous pain (Coghill, Sang, Maisog, & Iadarola, 1999). These activations could be associated with the need, during PET scanning, to willfully suppress scratching or withdrawal or breathing efforts. The thalamus and lentiform nucleus also were activated during dyspnea; these structures also are part of the pathway relaying pain and other sensations to the cortex (Casey, Minoshima, Morrow, & Koeppe, 1996; Coghill et al., 1999; Jones et al., 1991). It will require further studies to fully describe the cerebral correlates of dyspnea and to determine whether the activations for pain and dyspnea are identical or simply close neighbors. Unanswered questions about dyspnea suggested by the study of pain Multicomponent models of pain have been very useful in advancing the understanding of pain (Melzack & Casey, 1968; Price, 2000). The separation of unpleasantness from discriminative intensity responses to pain has provoked a great deal of study, in part because it has practical value in developing methods of pain relief and because distress caused by unpleasantness motivates patients to seek medical attention. We do not know whether the concept of separable unpleasantness and discriminative components can be usefully applied to dyspnea. This is an attractive idea that could reveal common mechanisms underlying response to all unpleasant stimuli, yet it is not a foregone conclusion. Pain transmission can be modulated at all stages from primary afferent to cognition; the ability to suppress pain probably confers an evolutionary advantage, for instance when escape or other homeostatic functions take priority over protection of injured sites. We often see athletes in important competitions perform with injuries that would produce unbearable pain in other circumstances. The ability to suppress air hunger must lose adaptive advantage when the oxygen supply is outstripped. Thus, we do not see underwater synchronized swimming routines exceeding a few minutes even in toplevel competition. Apart from intuitive examples such as this, we know very little about the possibilities for modulation of dyspnea. Perception of pain can, for instance, be strongly modulated by direction of attention toward or away from the painful stimulus (Miron, Duncan, & Bushnell, 1989). Although distraction can prolong breath hold for a matter of seconds (Bartlett, 1977), it is not known whether one can cause prolonged alterations of the intensity of dyspnea through attention. One study suggests that in experiments of several minutes duration, attention cannot be directed away from dyspnea by pain (Nishino et al., 1999), although pain is a potent distracter (Miron et al., 1989). If true, this is an important difference in forebrain processing between pain and dyspnea. Likewise, there is little information on modulation of

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