Historical Overview
Pain Defined
Pain is a subjective and entirely individually personal experience influenced by learning, context, and multiple psychosocial variables. Pain is not merely the end product of peripheral receptor stimulation and afferent signaling, but a complicated dynamic process of neural interplay with the noxious environment along ascending and descending peripheral, spinal cord, and brain networks. The International Association for the Study of Pain (IASP) defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” Pain serves an adaptive function, a warning system designed to protect the organism from harm. With chronicity and neuraxial pathology, however, the nociceptive system can become maladaptive and reflect endogenous pathology instead of an exogenous state. Acute pain is usually a response to a “noxious” event (i.e., a mechanical, thermal, or chemical insult) causing depolarization of the nonspecialized transducers (the nociceptors). It is time-limited, and treatment should be aimed at removing the underlying pathologic process. Concurrent behaviors will be designed to avoid or remove the offending noxious stimulus. In contrast, chronic pain is designated 3 to 6 months after the initiating event and in many cases might not be associated with any obvious ongoing noxious event or pathologic process. Behavior can become pathologic as attempts to avoid the noxious element fail, fight or flight responses escalate to no purpose, and so on. Chronic pain can differ from acute pain conditions in that underlying tissue pathology or injury begins to less directly correlate with levels of pain report. Whereas acute pain can be considered a physiologic response to tissue trauma or damage, chronic pain involves a more dynamic interplay of additional psychological and behavioral mechanisms ( Table 37-1 ). Chronic pain is often associated with disrupted sleep and declining function and eventually can cease to serve any protective role. At this point, pain can become a source of dysfunctional behaviors, suffering, and disability, often completely perplexing to the patient as well as to the unprepared physician.
| Characteristic | Acute | Subchronic | Chronic |
|---|---|---|---|
| Duration | Seconds | Hours to days | Months to years |
| Temporal features | Instantaneous and simultaneous to cause | Resolves on recovery | Persistent, long-term disease; may exceed resolution of tissue damage |
| Major characteristics | Proportional to cause | Primary and secondary hyperalgesia, allodynia, spontaneous pain | Subchronic characteristics plus paresthesias, dysesthesias, pronounced affective component |
| Class | Nociceptive | Principally nociceptive, neuropathic | Principally neuropathic, nociceptive |
| Source of pain | Transient nociceptive activation | Peripheral and central mechanisms | Peripheral and central mechanisms |
| Adaptive value | High, preventive | Protective, recovery | None, maladaptive |
| Adaptive response | Withdrawal, escape | Quiescence, avoidance of contact with injured tissue | Cognitive behavioral, catastrophizing, pain-related anxiety and fear, helplessness |
| Examples | Contact with hot surface | Inflamed wound | Chronic low back pain, muscle pain syndromes |
Environmental and affective factors can contribute to the persistence of pain and subsequent illness behaviors. The individual’s subjective response to chronic pain is shaped by the cognitive repertoire involved in attending to and anticipating noxious sensory signals as well as in appraising events associated with those signals ( Figure 37-1 ). Chronic painful conditions, when left untreated, can result in multiple problems, including unnecessary personal suffering for the patient, increased medical care use, overuse or misuse of psychoactive medications, iatrogenic complications secondary to inappropriate surgeries, excess disability, comorbid emotional problems (including increased risk of suicide), and increased economic and social costs. A multidisciplinary approach that addresses psychosocial and biological factors and focuses on functional restoration in all areas of life is sine qua non .
The prepared physiatrist can offer a unique perspective and skill set to the assessment and management of chronic pain and the psychosocial sequelae. The rehabilitative interdisciplinary team approach, a model for the treatment of other chronic disability conditions (e.g., spinal cord injury, stroke-related disorders, and amputee-related conditions), is focused on maximizing independent physical function, improving psychosocial state, and returning patients to work and previous leisure pursuits, as well as maximizing patients’ reintegration into the community and subsequent improvement of general quality of life. To achieve these ambitious goals, as well as adding the goal of decreasing the pain to tolerable levels, the physiatrist must thoroughly understand and appreciate the biological, psychological, and socioeconomic implications of pain and pain-related disability. A list of pain terminology and definitions is included for review ( Table 37-2 ).
| Term | Definition |
|---|---|
| Addiction | A chronic biopsychosocial disease characterized by impaired control over drug use, compulsive use, continued use despite harm, and craving |
| Allodynia | Pain caused by a stimulus that does not normally provoke pain |
| Analgesia | Absence of pain in response to stimulation that would normally be painful |
| Central pain | Pain initiated or caused by a primary lesion or dysfunction in the central nervous system |
| Dependence | A maladaptive pattern of drug use marked by tolerance and a drug class–specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood levels of drug, or administration of an antagonist |
| Dysesthesia | An unpleasant abnormal sensation, whether spontaneous or evoked |
| Hyperalgesia | An increased response to a stimulus that is normally painful |
| Hyperesthesia | Increased sensitivity to stimulation, excluding the special senses |
| Neurogenic pain | Pain initiated or caused by a primary lesion, dysfunction, or transitory perturbation in the peripheral or central nervous system |
| Neuropathic pain | Pain initiated or caused by a primary lesion or dysfunction in the nervous system * |
| Nociception | A receptor preferentially sensitive to a noxious stimulus that would become noxious if prolonged |
| Noxious stimulus | A noxious stimulus is one that is damaging to normal tissues |
| Pain | An unpleasant sensory and emotional experience associated with actual or potential tissue damage |
| Paresthesia | An abnormal sensation, whether spontaneous or evoked, that is not unpleasant |
| Peripheral neurogenic pain | Pain initiated or caused by a primary lesion, dysfunction, or transitory perturbation in the peripheral nervous system |
| Peripheral neuropathic pain | Pain initiated or caused by a primary lesion or dysfunction in the peripheral nervous system |
| Psychogenic pain | Pain not caused by an identifiable, somatic origin and that may reflect psychological factors |
| Tolerance | A state of adaptation in which exposure to a drug induces changes that result in diminution of one or more of the effects of the drug over time |
* See also neurogenic pain and central pain. Peripheral neuropathic pain occurs when the lesion or dysfunction affects the peripheral nervous system. Central pain may be retained as the term when the lesion or dysfunction affects the central nervous system.
This chapter offers the foundation for comprehensive pain management skills; a review of historical aspects that shaped the field of pain management and research; a review of our current understanding of both physiologic and pathophysiologic mechanisms of pain, the impact of psychosocial factors on the experience of pain, and their role in pain assessment and treatment; and a review of multidisciplinary treatment options that pertain to various chronic pain conditions. A multidisciplinary approach will be proposed as unequivocally the best model for successful and comprehensive chronic pain management.
Prevalence
Chronic pain and related suffering and disability represent an accelerating public health concern with considerable impact on the U.S. economy. Prevalence rates of chronic pain vary widely, from 2% to 55% in general population studies, and many pain-related conditions (i.e., osteoarthritis and spine-related conditions) accounting for a large proportion of reported pain and correlate with a high concurrent risk for disability.
Reviews of chronic pain as a secondary problem in patients with a primary disability, such as spinal cord injury, amputation, cerebral palsy, and multiple sclerosis, have demonstrated even higher prevalence rates of intolerable pain (greater than 70%), which can substantially add to disability. Pain associated with rehabilitation diagnoses is often reported in multiple sites, not just the focal site of the primary injury, and can contribute to a more generalized loss of function and related disability.
Cost of Chronic Pain
The progression from acute to chronic pain inevitably includes a greater impact in related psychological and social functioning. Chronic pain-related impairment and disability have significant socioeconomic consequences as a result of high health care costs, lost wages and productivity, and the growing costs of disability benefits and other compensation. Chronic pain is responsible for 90 million physician visits, 14% of all prescriptions, and 50 million lost workdays per year. Stewart et al. found that 75% of pain-related productivity loss was on the job, not a result of absence from work.
Early History of Pain Theory: A Peripheral Perspective
The development of pain medicine as a more formal science has been closely related to advancements in pain theory. Understanding historical factors related to the works of scientists and physicians can help the clinician better understand the complexities of the multidimensional experience of pain and suffering. The following is an overview of key factors related to pain theory, beginning with specificity theory up through and including contemporary theories.
The dualistic or mind-body controversy started with the biomedical theories of René Descartes (1596-1650) and can be seen as a precursor to specificity theory. He likened the pain system to a bell-ringing mechanism. The individual on the ground pulls the rope, ringing the bell in the tower. Similarly, placing the foot next to a burning flame would set particles in the foot in motion, traveling up the leg, back, and to the head, causing activation of pain. This theory, traditionally ascribed to Descartes, actually has earlier antecedents of Galen, based on the central position of the pineal gland, the center of the soul, and the sensory motor system.
The specificity theory remained somewhat unchallenged until the nineteenth century, with the emergence of physiology as a more formal scientific field of study. Claude Bernard (1813-1878) was the first to publish observations about the relationship of the autonomic nervous system to pain, and one of his students, the American Civil War surgeon Silas Weir Mitchell, would go on to elucidate what he called causalgia (now called complex regional pain syndrome type 2). The qualities of pain experience were thought to be associated with properties of sensory nerves. Johannes Müller was the first to elaborate on more specific neural pathways for pain in his theory of specific nerve energies (1842) as well as a distinction of four major cutaneous modalities (i.e., touch, warmth, cold, and pain), each with its own projection system to the brain.
With the evolution of the microscope, Max von Frey proposed the presence of cutaneous sensitivity maps on the skin, and although later disproved, described specific pain receptors. Today, his legacy includes von Frey filaments and von Frey hairs, important bedside sensory testing modalities.
In the 1870s, in a movement away from specificity theories, Erb proposed the intensive (summation) theory, in which individual sensory transducers were capable of producing pain only if the stimulus reached a sufficient intensity. Goldscheider later (1894) refined the stimulus intensity and summation theories and proposed the pattern theory. In pattern theory, pain results after total output at the cellular level reaches a critical level, either by stimulation by nonnoxious stimuli or by pathologic conditions that enhance summation. The theory centered on the contention that all nerve fibers are alike, and that pain is produced by spatiotemporal patterns of neuronal impulses versus activity on “specific” nerve fibers.
Central Theories of Pain
Until the late 1800s, pain theory was based primarily on peripheral mechanisms and failed to explain persistent pain states. The work of William Livingston with injured soldiers in World War II, and later in chronic work-related injuries, suggested that some portion of chronic pain mechanisms might be related to more specific central nervous system dysfunction. The summation theory by Livingston stated that pathologic stimulation of sensory nerves after nerve injury could lead to reverberating circuits in neuron pools of the spinal cord, which could later be triggered by peripheral nonnoxious inputs. This volley of nerve impulses could lead to a vicious cycle between central and peripheral processes.
Although debate continued among three basic pain theories, specificity ultimately prevailed and was universally accepted and practiced. An appreciation for cognitive and psychological aspects of pain processing, although secondary, slowly emerged within the fourth theory of pain, proposed by Hardy, Wolff, and Goodell. Pain was separated into two components: the perception of pain (afferent) and the reaction to pain (efferent). Pain perception was thought as a more hardwired physiologic process, whereas reaction to pain was under the influence of complex psychological and physiologic processes influenced by past experiences, the environment, and emotional state.
The Dutch surgeon Willem Noordenbos suggested that pain transmission was not a one-to-one synaptic transmission system but rather involved a multisynaptic modification process with complex interactions (such as convergence) between synapses. The sensory interaction theory of Noordenbos (1959) proposed two systems involving transmission of pain and other sensory information: a slow system (unmyelinated and thinly myelinated fibers) and a fast-acting system (large myelinated fibers). Large fibers could inhibit transmission of impulses from small fibers. This set the stage for the seminal work of Melzack and Wall on the gate control theory of pain modulation in 1965. Although controversial then and now, it brought an emphasis to a more convergent view of central pain processing at the spinal cord and cerebral levels.
The gate control theory by Melzack and Wall championed a more convergent view of pain processing. The spinal cord is not just a passive conduit for pain transmission but also an active modulator of pain signals. Activity in large myelinated afferent fibers theoretically activates dorsal horn encephalitogenic interneurons that inhibit cephalad transmission in small unmyelinated primary afferent nociceptive fibers and the secondary transmission cells in the lateral spinothalamic tracts. Somatic afferents activate convergent wide dynamic range cells deep in the dorsal horn (lamina V), which project in the spinothalamic tract to higher somatosensory processing in the thalamus and cortex. In theory, inhibiting pain by rubbing the skin activates large-diameter afferents inhibiting small-diameter fiber activation of wide dynamic range cells—that is, “closing the gate.”
Additional work 3 years later by Melzack and Casey emphasized motivational, affective, and cognitive aspects of the pain experience. Neural pathways could activate both sensory discriminative information about the location and intensity of pain, as well as more emotional and motivational effects of pain experience. Descending inhibition from cortical structures could also influence pain. Descending modulation of the gate theoretically could block nociceptive signals at the dorsal horn and provide the basis for behavioral-induced reduction of pain. In turn, psychological processes such as depression could potentially increase pain by “opening” gating mechanisms at the dorsal horn. This modulation, carried down to the dorsal horn in the dorsolateral funiculus and ramifying throughout the entire neuraxis, provides a way for the central nervous system to actively modulate the afferent input at multiple levels of the central nervous system. This affects all aspects of the pain experience, including affective, subjective, and evaluative components. The gate control theory offered a new model for the successful integration of experimental and clinical observations related to the study of pain. The gate control theory, although challenged as somewhat incomplete, has remained the core of contemporary pain science. It has spurred the development of new clinical treatments, including neurophysiologically based procedures (transcutaneous electrical nerve stimulation, spinal cord stimulation), and pharmacologic, cognitive, and behavioral treatments.
Melzack has extended his work with the gate control theory to include the more central neuromatrix theory based on concepts from cognitive neuroscience network theory. Dimensions of the pain experience are considered as output of the neuromatrix, which proposes a neurosignature of pain experience that is unique to each individual and is influenced by sensory, psychosocial, and genetic factors. This pattern is modulated by various sensory inputs from the environment and by cognitive events such as psychological stress. In turn, these multiple parallel processing inputs contribute to the sensory, affective, and cognitive dimensions of the pain experience and subsequent behavior.
Recent advances in neuroimaging and the exploding field of neuroscience networking have offered greater insight into higher-level cerebral plasticity related to acute and chronic pain. Apkarian et al. studied brain morphologic changes with the use of high-resolution magnetic resonance imaging in a group of patients with chronic low back pain. Significant evidence of discrete central nervous system degeneration (gray matter atrophy) in the chronic pain patient group was demonstrated. Discrete thalamic and prefrontal cortex atrophy was reported at a rate approximately 5 to 10 times greater than that of normal age-related atrophy. This underscores the importance of appropriate and aggressive treatment of pain as a means of preventing possible long-term or permanent central nervous system changes. In addition, these findings add to the ongoing developments in neural plasticity of pain because these changes are not plastic but are perhaps permanent ( Figure 37-2 ). The use of positron emission tomography and functional magnetic resonance imaging has offered accelerating insight into the main cerebral components of human nociceptive processing and networking at the brain and spinal cord levels.
History of Contemporary Advancements in Psychological Aspects of Pain
The twentieth century also provided significant growth in the fields of psychiatry and psychosomatic medicine. Sigmund Freud emphasized the potential link between psychological and physical factors in a number of medical conditions. Later, disenchantment with Freud’s psychoanalytic principles led to the development of the field of psychosomatic medicine and the subsequent rapid development of the fields of health psychology and behavioral medicine in the 1970s. Physicians such as George Engel (1959) challenged the biomedical model of disease as inadequate, in that it failed to include the social, psychological, and behavioral dimensions of illness. A classic article by Engel, “ ‘Psychogenic’ Pain and the Pain-Prone Patient,” discussed various contextual meanings of persistent pain and the importance of an individual’s interpretation of his or her pain. Sternbach argued that physiologic and affective perceptions of pain should be understood as learned responses under the control of environmental forces and addressed psychophysiologic pain syndromes, including “stress-induced pain disorders.” Wilbert Fordyce later proposed an operant conditioning model of chronic pain based on an ends approach of identifying and treating pain behaviors. More recently, higher cognitive functioning in pain states (such as memory and emotive components) were embraced in the cognitive behavioral approach, led by health psychologists such as Dennis Turk and Frances Keefe, emphasizing the role of attributions, efficacy, personal control, and problem solving. Thoughts and beliefs could influence, and be influenced by, emotional and physiologic responses. This has contributed to the evolution of a more clinically pragmatic school of pain assessment and treatment: the biopsychosocial model. This model incorporates the physical, cognitive, affective, and behavioral components related to ongoing pain experience. In this context, biological factors can initiate a physical disturbance, but psychosocial factors often influence pain perception, pain behavior, and the ongoing pain experience.
Physiology and Pathophysiology of Pain
In a normal homeostatic state, cutaneous, visceral, and musculoskeletal pain serve as an alarm system to the body that indicates damage or potential damage in the environment. The purpose of nociception is to alert the organism to this potential damage so that avoidance behavior can be initiated. In contrast, chronic pain states might represent an alteration involving damage or injury to the central nervous system that serves no real protective role, reflecting a pathologic as opposed to physiologic state. The complex interaction between the initial stimulus of tissue injury and the subjective experience of nociception and acute and chronic pain can be described by four general processes known as transduction, transmission, modulation, and perception ( Table 37-3 ).
| Stage | Description |
|---|---|
| Transduction (receptor activation) | One form of energy (thermal, mechanical, or chemical stimulus) is converted electrochemically into nerve impulses (action potentials) in primary afferents |
| Transmission | Coded information is transferred from primary afferent fibers to spinal cord dorsal horn and onto brainstem, thalamus, and higher cortical structures |
| Modulation | Involves activity- and signal-induced dorsal horn neural plasticity, which includes altered receptor and channel function (i.e., wind-up and central sensitization), gene expression, and changes in brain-mediated descending inhibition and facilitation |
| Perception | Begins with activation of sensory cortex. The cortex is in intimate communication with motor and prefrontal cortices, which initiate efferent responses, as well as more primitive structures involved in the emotive aspects of pain |
Normal pain, or nociception, is characterized primarily by the processes of transduction and transmission, with minimal emphasis on modulation and a “normal” perception process. With chronic or persistent pain states, there is a shift of focus to the processes of modulation and perception. These four general processes are reviewed in the following sections and serve as an important foundation for a more clear understanding of complex pain mechanisms and possible rational pharmacotherapeutic, interventional, and cognitive behavioral treatment approaches.
Transduction
The principal receptors for pain are the branched endings of C and Aδ fibers ( Table 37-4 ) in the skin, muscles, and joints. Damaging (or potentially damaging) energy in the cellular environment impacts the free nerve endings, and the complicated cellular processes of nociceptive transduction occur. Inflammatory cascades are concurrently activated (e.g., prostaglandin, leukotriene) and immediately become principal players in the transduction process. Recent histochemical studies have revealed two broad categories of C fibers: peptidergic and isolectin B 4 binding. Peptidergic fibers contain a variety of peptide neurotransmitters, including substance P and calcitonin gene-related peptide (CGRP), and express tyrosine receptor kinase A receptors, which show high affinity for nerve growth factors. Peptidergic neurons appear to be key players in neurogenic inflammation (where the transduction cells themselves become active participants in the local inflammatory process) and other chronic inflammatory states. The other class, isolectin B 4 binding, contains few neuropeptides but expresses a surface carbohydrate group selectivity binding to the plant lectin isolectin B 4 and is supported by glial-derived neurotrophic factor. Isolectin B 4 expresses P2X3 receptors, a subtype of ATP-gated ion channels. Differences in supporting trophic factors might be responsible for differing functional responses to painful stimuli between these distinct C-fiber types. Neurotrophins have emerged as potential factors for activity-dependent changes at the synapse and possibly subsequent central nervous system plasticity.
| Sensory and Motor Fibers | Sensory Fibers | Diameter (µm) | Myelinated | Velocity (m/s) | Motor Function | Sensory Function |
|---|---|---|---|---|---|---|
| Aα | 1a | 10-20 | Yes | 0-120 | α-Motor neurons | Muscle spindle afferents |
| 1b | 10-20 | Yes | 50-120 | — | Golgi tendon organs, touch, pressure | |
| Aβ | 2 | 4-12 | Yes | 25-100 | Motor neurons to intrafusal and extrafusal muscle fibers | Secondary muscle spindle afferents, touch, pressure, vibration |
| Aγ | 2-8 | Yes | 10-50 | Motor neurons to intrafusal muscle fibers | — | |
| Aδ (types 1 and 2) | 3 | 1-5 | Lightly | 3-30 | — | Touch, pain, and temperature |
| B | 1-3 | No | 3-15 | Preganglionic autonomic fibers | — | |
| C | 4 | <1 | No | 0.5-2 | Postganglionic autonomic fibers | Pain and temperature |
Multiple arachidonic acid residue receptors are probably involved (e.g., prostaglandin, leukotriene), and the “chaos” level of complexity is further complicated by the very active presence of the support cells (glia and myelin) and the efferent input by the central nervous system itself, primarily via the sympathetic nervous system. Noradrenergic receptors are on the transduction cell, and these can be “uncovered” or activated in inflamed tissue.
Aδ nociceptors (also responders to noxious, thermal, and chemical stimuli) are most easily classified on functional grounds. Type 2 Aδ exhibit short response latencies to heat and are activated at relatively higher thresholds (43° C). Type 2 Aδ are responsible for the initial sensation of a burn stimulus. Type 1 Aδ exhibit longer response latencies and are activated at much higher temperatures (greater than 50° C). Type 1 Aδ and nociceptive C fibers are more commonly associated with persistent painful sensations.
Transmission
Cutaneous peripheral afferent neurons can be classified into three types based on diameter, structure, and conduction velocity of action potentials. In general, C fibers (thin, unmyelinated, slowly conducting; 0.5 to 2.0 m/s) and Aδ fibers (medium, thinly myelinated, rapidly conducting; 12 to 30 m/s) carry noxious stimuli, and Aβ fibers (large, myelinated, and fast; 30 to 100 m/s) carry innocuous stimuli (touch, vibration, and pressure), except in situations of peripheral or central sensitization (see Table 37-4 ). The percentage of distribution of nociceptors in the skin is roughly proportioned 70%, 10%, and 20%, respectively. With peripheral and central neuroplastic changes in Aβ fibers, innocuous stimuli might be perceived as painful, resulting in allodynia. Aδ nociceptors respond to intense mechanical and temperature stimuli, and with sensitization contribute to the process called hyperpathia, in which noxious stimuli become frankly more painful and the pain perception can last longer, even after the initial stimulus is removed. Most C fibers are polymodal transducers. Aβ fibers demonstrate encapsulated nerve endings involved in nonnociceptive function. Aδ fibers mediate the fast, prickling quality of pain, whereas C fibers mediate the slow, burning quality of pain. An additional class of nociceptors, the so-called silent or sleeping nociceptors, makes up approximately 10% to 20% of C fibers in the skin, joints, and viscera, and is normally unresponsive to acute noxious stimuli. With inflammation and tissue injury, these “silent” nociceptors are sensitized via activation of second-messenger systems and the release of a number of local chemical mediators (i.e., bradykinin, prostaglandins, serotonin, and histamine) and can contribute to temporal and spatial summation, increasing afferent input at the dorsal horn.
Peripheral Sensitization
C fibers and Aδ receptors undergo changes in response to tissue injury such as inflammation, ischemia, and compression. These changes are marked at the peripheral terminals by the release of chemical mediators from damaged and inflammatory cells. The so-called inflammatory soup, rich in analgesic substances, causes a lowering of threshold for activation and subsequent evoked pain. Algogenic substances also activate second-messenger systems, which induce gene expression in the cell. Excitatory amino acids and neuropeptides (substance P, CGRP, and neurokinins) are released by peripheral and central nociceptive C fibers, inducing neurogenic inflammation. Neurogenic inflammation involves retrograde release of algogenic substances, which in turn excites other nearby nociceptors, creating local feed-forward loops of sensitization and activation.
Modulation
Primary afferents subserving distinct input from cutaneous, muscle, and visceral tissues converge at the dorsal horn. Several ascending pathways are involved in transferring and modulating this nociceptive input. At the cellular level, the influx of sodium is fundamental to electrical signaling and subsequent generation of action potentials and excitatory postsynaptic potentials. This is followed by calcium channel opening, contributing to more prolonged depolarization, as well as second-messenger molecular changes involved in more permanent neuroplastic central nervous system changes. At the synaptic terminal of the axon, action potentials lead to the release of neurotransmitters. Neurotransmitter release depends on specific ion channels, which are either ligand-gated, opening in response to binding of ligands to receptors, or voltage-gated, opening in response to changes in membrane potentials. Other targeted receptor and ion channels include vanilloid (capsaicin) receptor, heat-activated, ATP-gated purinergic receptor (P2X), proton-gated or acid-sensing ion channels, and voltage-gated sodium channels. The vanilloid receptor is a nonselective cation channel (vanilloid receptor 1) activated by elevated temperature (greater than 43° C) and acidification.
Aδ and C fibers convey nociceptive information primarily to superficial laminae (I and II) and deep laminae (V and VI) of the dorsal horn. Lamina I plays an important role in relaying information on the current state of tissues, including damaging mechanical stress, heat and cold, local metabolism (acid pH, hypoxia), cell breakdown (ATP, glutamate), mast cell activation (serotonin, bradykinin), and immune activity (cytokines). Aβ fibers transmit innocuous, mechanical stimuli to deeper laminae (III to VI). Lamina I cells are activated by nociceptive-specific neurons, whereas lamina V cells respond to wide dynamic range neurons of “wide” stimulus intensities. Wide dynamic range neurons receive input from mechanoreceptive Aβ fibers and nociceptive (Aδ and C) fibers ( Figure 37-3 ). Normal synaptic transmission conduction of action potentials at the dorsal horn initiates neurotransmitter release. Low-intensity stimulations (i.e., brush, touch, or vibration) activate Aβ fibers only, releasing fast, glutamate-mediated postsynaptic currents. Fast excitatory transmission glutamate is coreleased presynaptically with neuropeptides such as substance P, CGRP, cholecystokinin, proteins (brain-derived neurotrophic factor), and glial-derived factors. Glutamate acts on a range of transmission cell receptors, such as N -methyl- d -aspartate (NMDA) (slow current), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (fast current), metabotropic glutamate receptors, and kainate ligand-gated ion channels. With normal transmission, sodium flows only through the AMPA receptor, whereas the NMDA receptor is blocked by magnesium. Prolonged depolarization of the postsynaptic cell causes voltage-dependent magnesium removal, opening the channel and allowing additional sodium and calcium to enter the cell. This amplified evoked response to subsequent input describes the process of wind-up.
Central Sensitization
The term central sensitization describes a complex set of activation-dependent posttranslational changes occurring at the dorsal horn, brainstem, and higher cerebral sites. For example, at the dorsal horn, nociceptors release neurotransmitters (glutamate, substance P, and brain-derived neurotrophic factor) onto the transmission cells, which results in changes in activation of related receptors and channels (as described earlier). This results in an increase in calcium influx (and efflux from cytoplasmic organelles), contributing to potentiation of the cell by activation of calcium-dependent enzyme protein kinases (e.g., protein kinase C, cyclic AMP, and tyrosine receptor kinase). Posttranslational changes also include phosphorylation of NMDA and AMPA receptors, activation of second messengers such as nitric oxide, and central prostaglandin production.
Ascending and Descending Modulation
Melzack & Casey’s classic descriptions of neuroanatomic pathways make a distinction between the lateral and medial pain systems corresponding to their relationship with the thalamus. The two systems are highly interdependent, the lateral (neospinothalamic) system generally representing sensory-discriminative dimensions versus the medial (paleospinothalamic) system involving more motivational-affective and cognitive-evaluative dimensions of the pain experience. Additional ascending pathways, including the spinothalamic, spinomesencephalic, spinoreticular, spinolimbic, spinocervical, and dorsal column pathways, are described elsewhere.
The lateral system projects to the ventral posterolateral and ventral posteromedial thalamic nuclei before projecting to the somatosensory and premotor cortices. The motor input is nearly as large as the sensory input, and this theoretically prepares the recipient of the painful input for the appropriate efferent (behavioral) response. The more medial pathway projects to the medial thalamic nuclei and limbic cortices, which include the anterior cingulated cortex, orbitofrontal cortex, and amygdala. The medial system involves important connections with periaqueductal gray, a key area involved in modulating nociceptive inhibition and behavioral responses to potentially threatening stimuli. Animal and human studies have identified the anterior cingulated cortex in regulating avoidance behaviors and the perception of pain unpleasantness. Only a small proportion of these action potentials normally reach the thalamus and higher brain centers as a result of significant modulating or filtering effects at the spinal cord and brainstem. Of course, with prolonged disease and inflammation these filters “break down,” contributing to central sensitization.
In addition to descending inhibition, the endogenous inhibitory system also includes local endogenous opioids (from periaqueductal gray), biogenic amines (serotonin and noradrenaline [norepinephrine]), and γ-aminobutyric acid (GABA), which generally act to inhibit pain signals. Important excitatory transmitters in this system include glutamate and substance P. Besides descending inhibition from cortical areas, recent studies have suggested that descending facilitatory pathways might link brainstem and spinal cord areas via pronociceptive serotonergic and opioid mechanisms. These pronociceptive pathways could help explain the possible mechanism of persistent pain signs and symptoms, such as allodynia and hyperalgesia, that are common to chronic pain conditions.
Pathways originating from the spinal cord dorsal horn activate brain structures involved in rudimentary aspects of the autonomic system response (i.e., escape, arousal, and fear), including the medulla and midbrain reticular formation, amygdala, hypothalamus, and thalamic nuclei. Activation of somatosensory cortices (S1 to S2) provides information regarding the quality and intensity of pain. Affective aspects of the pain experience, such as pain unpleasantness, reflect more of the aversive qualities of the pain experience, such as the suffering component. Higher processing involves parietal and insular regions, contributing to an overall sense of intrusion and unpleasantness. Finally, convergence of these pathways with more frontal regions, such as the anterior cingulate cortex, is responsible for attention and emotional valence of the overall pain experience.
Although cutaneous and visceral pain share common cortical and subcortical networks, differences in response pattern, frequency, and processing might underlie differences in quality, affect, and resultant behavioral responses. Visceral pain has a more indistinct quality, poor localization, and in general is associated with autonomic markers such as bradycardia and hypotension. Cutaneous nociceptive reactions more classically involve protective reflexes such as tachycardia and hypertension.
Psychological Issues Related to Chronic Pain
The physiatric approach to chronic pain conditions must include an understanding of the wide array of important psychological (affective and cognitive) factors that affect the multidimensional experience of pain. Psychological factors can serve to decrease or increase the subjective perception of pain and adjustment to ongoing pain-related disability. Affective factors usually include more negative emotions, such as depression, pain-related anxiety, and anger. Cognitive factors include catastrophizing, fear, helplessness, decreased self-efficacy, pain coping, readiness to change, and acceptance.
Affective Factors
Depression
A strong association between chronic pain and depression has been suggested. The prevalence estimates of major depression in patients with chronic pain conditions vary from 5% to 87%, and this variation could be attributable to a number of analytic factors, including the diagnostic criteria used, type of pain studied, and selection bias. Somatic symptoms of major depressive disorder can also be common in patients with chronic pain (i.e., change in appetite, change in weight, loss of energy, and sleep disturbance). The incidence of depression among patients with chronic pain can be higher than with other chronic medical conditions. The presence of chronic pain might be related to longer durations of depressive symptoms. In general, most systematic reviews on the relationship between pain and depression suggest that chronic pain precedes depression. Predictors of depression in chronic pain include pain intensity, number of painful areas reported, frequency the severe pain is experienced, and a number of related psychosocial factors. Patients with depression can report higher levels of pain, be less active, report greater disability and life interference related to pain, and are more likely to display overt pain behaviors. Brown et al. examined the mediating factors of the relationship between chronic pain in patients with rheumatoid arthritis and decreased cognitive functioning, which included measures of inductive reasoning and working memory. Elevated depression mediated the relationship between higher levels of pain and reduced cognitive functioning, underscoring the importance of the complex relationship among depression, chronic pain, and functional impairment.
Anxiety
Anxiety related to pain is an important factor involved in maladaptive responses, behavioral interference, and affective distress. Heightened pain-related anxiety has been described as one of the most disabling aspects of ongoing chronic pain. It is closely related to avoidance activities (discussed later), which serve to promote ongoing pain, physical deconditioning, and social isolation. Anxiety as a psychological construct in chronic pain has been developed by McCracken et al. as pain-related anxiety. Pain-related anxiety encompasses fear reactions across the cognitive, behavioral, and physiologic dimensions of pain. In chronic pain, it has been found to be a significant predictor of pain severity, disability, and pain behaviors.
Anger
Ongoing failure to achieve pain relief and repeated unsuccessful attempts to escape pain have been shown to be associated with increased levels of anger and physiologic responses to pain, independent of pain intensity. In a study of patients presenting for chronic pain management, Okifuji et al. reported 70% of participants with angry feelings, most commonly with themselves (74%) and health care professionals (62%). In this study, anger toward oneself was associated with pain and depression, whereas “only anger” was related to perceived disability.
Conceptualizations of anger in chronic pain vary. A more classic definition of anger has been described as a “feeling involving a belief that a person one cares for has, intentionally or through neglect, been treated without respect, and a want to have that respect reestablished.” Anger as a construct has also been considered to be related to personality dispositions associated with unconscious conflicts, or as a reaction to the presence of ongoing unrelieved pain. Others have suggested that chronic pain might develop as a conversion-like symptom to suppress feelings of anger, and suppressed anger could be negatively related to adjustment to ongoing chronic pain. In contrast, “anger out” has also been linked to poor adjustment. These styles of anger management, suppression (anger in) and expression (anger out), are distinguished from overt hostility. Hostility has been defined as “an attitude of cynical mistrustfulness, resentment, and interpersonal antagonism.” Burns has demonstrated how anger management style and hostility can affect maintenance and exacerbation of chronic low back pain via symptom-specific physiologic responses (i.e., increased muscle stress reactivity in lumbar paraspinals in patients with low back pain). This work was based on the studies of Flor et al., who showed that patients with chronic low back pain exhibited greater stress-induced increases in electromyogram readings in lower paraspinal muscles compared with normal individuals. Anger and related physiologic responses are additional targets for pharmacologic and behavioral treatments, including relaxation training and other mind-body treatments.
Cognitive Factors
Many patients with chronic pain demonstrate a reduction in goal-directed activities and assume a more passive sedentary lifestyle. This further contributes to a downward spiral of inactivity, deconditioning, and increased somatic focus. Individual responses to pain are recognized as important variables of the pain experience and can be associated with a greater risk of maintaining pain-related disability. Patients who frequently have excessively negative thoughts about themselves, others, and the future are more likely to experience high levels of depression, low levels of activity, and increased tension. Pain beliefs (pain-related fear and self-efficacy), anger, and passive coping are important affective factors, which can significantly affect pain response, behavior, and function. Other neurocognitive factors, unique to each patient, including attention, expectation or anticipation, and appraisals, can contribute to maladaptive behaviors and can represent important targets for cognitive and behavioral interventions.
Learning Factors
Operant Learning
Fordyce’s operant conditioning approach to pain serves as one of the earliest psychological models for chronic pain. The model focuses primarily on observable behavioral manifestations of pain, which are subject to both reinforcement and avoidance learning. When an individual is exposed to a stimulus that causes tissue damage, an immediate response occurs that involves withdrawal or attempts to escape the stimulus. By successfully avoiding pain (i.e., “punishment”), the individual achieves a reduction in pain, thus rewarding the avoidance behavior. The acquisition of pain behaviors can be determined initially by the history of learned avoidance behaviors. In these cases, pain becomes a discriminating stimulus signaling behaviors that are pain reducing, such as rest and analgesic medication consumption. With time, pain-eliciting situations such as movement and activity cause anticipatory fear and are avoided. Over time, pain avoidance behaviors can generalize to other potentially painful stimuli, contributing to more inactivity and passivity. In a similar way, verbal expression of pain (e.g., complaining) and nonverbal pain behaviors (e.g., limping and grimacing) can be maintained by external reinforcement contingencies such as subtle rewards by significant others or family members who respond to these behaviors.
Waddell et al. identified a set of “nonorganic” signs that can be used as a simple clinical screening tool to help identify signs and symptoms of pain behavior (tenderness, simulation, distraction, and regional sensory and motor impairments). Although controversial, a study of nonorganic signs in a group of patients with low back pain found that demonstration of at least three of the five signs correlated with psychological distress.
Fear of Movement
Kinesophobia, a term that describes an irrational and excessive fear of movement, physical activity, and reinjury, is exhibited by many patients with chronic pain. Fear of movement can be initially induced by classical conditioning but is reinforced through operant learning; by avoiding the conditioned anxiety and fear associated with movement, the patient never extinguishes the fear. It has been shown in studies to strongly correlate with other responses, such as catastrophic thinking and subsequent increased fear and avoidance behaviors, in patients with chronic low back pain. In this way, increased levels of fear and disability can occur independently of the experienced pain intensity. McCracken et al. found that increased fear and anxiety in patients with low back pain correlated with decreased range of motion and increased expectation of pain. Other studies in chronic low back pain have found pain-related fear and fear-avoidance beliefs as predictors of disability, decreased activities of daily living, and lost work time.
A cognitive behavioral model emphasizes two opposing behavioral responses: confrontation and avoidance. The conclusion of Waddell et al. that “fear of pain and what we do about pain can be more disabling than pain itself” underscores the importance of identifying and treating such maladaptive thinking and behavior in a physiatric approach to effectively managing chronic pain.
Behavioral Treatment Approaches
Operant Behavioral Techniques
Operant behavioral therapy refers to interventions focused on the observed behavior of the patient. As proposed by Fordyce, operant models of pain are based on both positive and negative reinforcement contingencies. Environment and social factors serve to maintain pain behaviors. For example, the verbal expression of pain and nonverbal pain behaviors (e.g., grimacing and guarding) can be maintained by both positive (attention from others, potential monetary gain) and negative reinforcement (nonoccurrence of aversive stimuli, avoidance of activity). Once identified, these behaviors serve as targets for treatment. Many times these behaviors need to be reinforced only intermittently. Operant behavioral therapy can be most useful and practical with patients demonstrating excessive pain behaviors despite limited tissue pathology, poor insight into the relationship of their own behavior and subjective experiences of pain, and operant-related issues (secondary gain).
Goals of operant behavioral therapy include encouraging the development and acquisition of more adaptive pain management strategies, which include establishing wellness behaviors and discouraging or reducing reinforcement of pain behaviors. The theory suggests that both wellness and pain behaviors can be shaped. Management techniques target unlearning these behaviors and serve as the basis of most functional restoration-based programs developed by Mayer and Gatchel. Operant behavioral therapy techniques are provided to patients in individual and group settings, focusing on helping patients to master and apply multiple strategies including pacing and graded exercise, scheduling and/or limiting pain medications and passive treatments, and counseling regarding negative and positive social reinforcement via spouse and family training.
Cognitive Behavioral Techniques
Cognitive therapy techniques are based on the notion that one’s cognitions can have an impact on mood, behavior, and physiologic function. Techniques used in pain management are designed to help patients notice and modify the negative thought patterns that contribute to ongoing pain and affective distress. These include cognitive restructuring, problem solving, distraction, and relapse prevention. Five primary assumptions underlie all cognitive behavioral therapy interventions ( Box 37-1 ). Cognitive behavioral therapy is a flexible, viable, and empirically validated approach for effectively treating patients with persistent pain.
- 1.
Individuals actively process information regarding internal stimuli and environmental events.
- 2.
Cognitions interact with emotional and physiologic reactions as well as with behavior.
- 3.
Reciprocal interactions occur between an individual’s behavior and environmental responses.
- 4.
Effective treatment interventions must address the cognitive, emotional, and behavioral dimensions of the presenting problem.
- 5.
It is necessary to help individuals become active participants in learning adaptive methods of responding to their problems.
Sleep and Chronic Pain
Sleep is a dynamic, complex physiologic process that is required for survival. During sleep there is decreased sensitivity to the external environment and increased activity of the parasympathetic nervous system. Sympathetic nervous system activity is similar to that in wakefulness, except for during periods of rapid eye movement (REM). Breathing is irregular, and control of body temperature is altered. Sleep comprises alternating REM and non-REM (NREM) states that cycle at an ultradian rhythm of approximately 90 minutes.
Sleep of 8 to 8.5 hours is considered restorative in adults. Sleep is entered through NREM, and the NREM-REM cycle occurs three to six times during a normal 8-hour sleep period. The determinants of sleep are numerous and include homeostasis, the circadian rhythm, control via the ventrolateral preoptic nucleus, age, drugs, external temperature, medical and psychiatric disease, and other environmental factors. The ventrolateral preoptic nucleus has been shown to contain GABAergic and galaninergic neurons that are necessary for normal sleep. Lesions to this region have been shown to decrease both REM and NREM sleep by 55%, verifying their function in inhibiting the firing of cells involved in wakefulness. These inhibited neurons contain the neurotransmitters histamine, norepinephrine, serotonin, hypocretin, and glutamate. Age represents a strong determinant of sleep, as time spent in stages 3 and 4 decreases by 10% to 15%, latency to fall asleep increases, and the number and duration of overnight arousal periods increase in older adults compared with young adults.
The interrelationship between disturbed sleep and chronic pain conditions is well documented for both adults and adolescents. Prevalence estimates of disturbed sleep range from approximately 50% to 90% depending on the clinical study population under evaluation. Although the nature of the relationship between pain and disturbed sleep is not well understood, a reciprocal association is suggested. Current research suggests a multifactorial relationship including depression, fear-avoidance behaviors, catastrophizing, and even treatments such as benzodiazepines and chronic opioid therapy. Patients with chronic pain can display frequent sleep fragmentation, longer sleep latency, and decreased overall quality of sleep. Sleep fragmentation is characterized by repetitive short interruptions in sleep and is a recognized factor in the cause of excessive daytime sleepiness. This inability to maintain sleep can be the most important factor in the treatment of disturbed sleep in individuals with chronic pain. The strength of this relationship between disturbed sleep and chronic pain cannot be underestimated.
Assessment
The assessment of chronic pain involves a thorough physical examination and a comprehensive evaluation of pain intensity and psychosocial factors related to ongoing pain experience and interference with sleep, daily activities, family life, and employment. Subjective reports of pain intensity are an important part of the initial assessment and subsequent visits and can include pain intensity numeric rating scales, visual and verbal analogue scales, and pain drawings. Self-monitored pain intensity ratings are both reliable and valid. Patient variability remains, however, when interpreting self-report measurement scales. A significant area of study has examined the level of change that best represents a clinically important improvement with the use of the numeric rating scale in monitoring pain response with drug treatment trials. Farrar et al. found that a reduction of approximately 30% represented a clinically important difference. A commonly used comprehensive measure of pain intensity, the McGill Pain Questionnaire Short Form, measures three dimensions of pain: sensory, affective, and evaluative. It uses 20 subclasses or groupings of pain adjectives, including sensory (e.g., “sharp,” “dull,” and “heavy”) and affective (e.g., “annoying,” “tiring,” and “exhausting”); it also includes pain drawings and the visual analogue scale.
Additional psychometric measures can also be included in the initial assessment focusing on psychosocial factors such as mood (depression, anxiety, and anger), attitudes, beliefs, functional capacity, activity interference, and personality traits ( Table 37-5 ). The use and combination of these different methods depend largely on the goal of the assessment. A semistructured interview by an experienced psychologist is the most comprehensive means of evaluating the psychological state of the patient. A pack of self-reported questionnaires completed by the patient before the evaluation, measuring a wide spectrum of the multidimensional factors related to pain, can be used in isolation or as an adjunct to the psychological and medical interview.
| Psychometric Measure | Psychometric Assessment Tool | Description | Reference |
|---|---|---|---|
| Pain intensity | Numeric Rating Scale | 0-10, 0-100, “no pain” to “worst pain” | — |
| Visual Analogue Scale | Straight line, 0-10 cm | ||
| Verbal Rating Scale | List of adjectives or descriptors | ||
| Pain affect | McGill Pain Questionnaire-Short Form (MPQ-SF) | 20 descriptors (sensory, affective, evaluative), pain drawing, visual analogue scale; 4-point Likert scale from 0 (none) to 3 (severe) | Melzack |
| Brief Pain Inventory (BPI) and Brief Pain Inventory-Short Form (BPI-SF) | Measures the impact of pain on everyday activities and mood | Cleeland and Ryan | |
| Anxiety and coping | Pain Anxiety Symptoms Scale (PASS) | 40 items; anxiety related to pain on 6-point scale, subscales: cognitive anxiety symptoms, escape and avoidance, fearful appraisals, physiologic symptoms | McCracken et al. |
| Spielberger State-Trait Anxiety Inventory (STAI) | 40 items; differentiates between the temporary condition of “state anxiety” and the more general and long-standing quality of “trait anxiety” | Spielberger et al. | |
| Survey of Pain Attitudes (SOPA) | 57-item, 5-point scale assessing control, disability, medical cures, solicitude, medication, emotion, and harm | Jensen et al. | |
| Depression | Beck Depression Inventory (BDI) | 21-item, 4-point scale assessing mood and neurovegetative dimensions of depression | Beck and Steer |
| Center for Epidemiologic Studies Depression Scale (CES-D) | Less compromised validity by somatic symptoms compared with the Beck Depression Inventory, more sensitive to changes in severity of depression | Radloff | |
| Zung Self-Rating Depression Scale | 20-item, rapid assessment tool for severity of depression | Zung | |
| Mood and personality | Minnesota Multiphasic Personality Inventory (MMPI) | 567 true-false items, 60-90 min to administer | Butcher et al. |
| Symptom Checklist 90 (SCL-90-R) | 90-item, 5-point scale, global index score, and 9 subscales of general emotional distress | Derogatis | |
| Millon Behavioral Health Inventory | 150 true-false items, assesses styles of relating to providers, psychosocial stressors, and response to illness | Millon et al. | |
| Functional capacity and activity interference | Sickness Impact Profile (SIP) | 136 items, 12 dimensions of function | Bergener et al. |
| 36-Item Short-Form Health Survey (SF-36) | Eight scales to measure limitations in physical and social activities caused by physical and emotional problems, bodily pain, vitality, and general health perceptions | Ware and Sherbourne | |
| West Haven-Yale Multidimensional Pain Inventory (WHYMPI or MPI) | 52-item, 7-point scale, 12 dimensions (pain experience, perceptions of others, common daily activities), classifies patients primarily into three classes (dysfunctional, interpersonally distressed, and adaptive copers) | Kerns et al. | |
| Pain Disability Index (PDI) | 7 questions: degree of interference with functioning, home, recreation, social activities, occupations, sexual behavior, self-care, and life support | Trait et al. | |
| Oswestry Disability Questionnaire | 10 sections, assesses the effect of back and leg pain on activities of daily living and patient’s everyday life | Leclaire et al. | |
| Coping and beliefs | Coping Strategies Questionnaire (CSQ) | 50 items, cognitive and behavioral coping strategies assessed | Rosenstiel and Keefe |
| Survey of Pain Attitudes (SOPA) | 57 items, subscales (control, disability, medical cures, solicitude, medication, emotion, and harm) | Jensen et al. |
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