Chapter 42 Chronic Pain
There are among us those who haply please to think our business is to treat disease.
And all unknowingly lack this lesson still ’tis not the body, but the man is ill.
Historical Overview
Pain Defined
Pain is a subjective and entirely individually personal experience influenced by learning, context, and multiple psychosocial variables.201 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.”203 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.265 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.219 Behavior can become pathologic as attempts to avoid the noxious element fail, fight or flight responses escalate to no purpose, etc. 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 psychologic and behavioral mechanisms (Table 42-1).48 Chronic pain often is 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.
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 42-1). 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 biologic factors and focuses on functional restoration in all areas of life is sine qua non.
FIGURE 42-1 Processes of chronic pain.
(Modified from Kidd BL, Urban LA: Mechanisms of inflammatory pain, Br J Anaesth 87:3-11, 2001, with permission.)
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 biologic, psychologic, and socioeconomic implications of pain and pain-related disability. A list of pain terminology and definitions is included for review (Table 42-2).
| 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 psychologic factors |
| Tolerance | A state of adaptation in which exposure to a drug induces changes that result in diminution of one or more of the drug’s effects 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.
From Merskey H, Bogduk N: IASP Task Force on Taxonomy classification of chronic pain: description of chronic pain syndromes and definition of pain terms, Seattle, 1994, IASP Press, with permission.
Prevalence
Chronic pain and related suffering and disability represent an accelerating public health concern and a fiscal “black hole” in the U.S. economy. Prevalence rates of chronic pain vary widely, from 2% to 55% in general population studies,43,74,121,309 and probably realistically represent 30% to 40%.5,29 Prosaic diagnoses (i.e., chronic arthritic and musculoskeletal conditions and spine-related disorders) account for a large portion of reported pain and correlate with a high concurrent risk for disability.326 By 2030, physician-diagnosed arthritis and related disability is predicted to affect 71 million Americans. Chronic pain is an important cause of health-related loss of productivity in the workplace, in addition to medical, pharmacy costs, and absenteeism, surpassing combined costs related to cancer, hypertension, and depression.165 Projected expansion of the elderly population, as well as increased survival rates of the disabled population and individuals with life-shortening or previously terminal conditions, will lead to further increases in prevalence.
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 (>70%), which can substantially add to disability. For example, a longitudinal study of chronic pain in adult cerebral palsy patients found that pain remained steady over a 2-year period, and that pain was unlikely to decrease spontaneously without treatment.132 Pain associated with rehabilitation diagnoses is often reported in multiple sites, not just the focal site of the primary injury,73,303 and can contribute to a more generalized loss of function and related disability.
The Cost of Chronic Pain
The progression from acute to chronic pain inevitably includes a greater impact in related psychologic 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.307 Conservative estimates of cost related to health care expenditure and lost productivity range from $70 to $120 billion annually.94,222 Chronic pain is responsible for 90 million physician visits, 14% of all prescriptions, and 50 million lost workdays per year.24,54 One third of the population suffers from chronic pain-related conditions, at a cost of $100 billion in related compensation, health care, and litigation costs.167 Stewart et al.287 found that 75% of pain-related productivity loss was on the job, not a result of absence from work.
History
The concept of pain has been part of the human experience closely woven into the cultural fabric of philosophy, politics, and religion since early times, including documented periods in ancient China, India, and Egypt. In a quest for analgesia and decreased suffering, individuals have tolerated rather barbaric and ineffective treatments, including purging, cupping, blistering, bleeding, leeching, heating, and freezing.271 In ancient Greece, Hippocrates (460 to 370 BC) hypothesized that four bodily fluids (“humors”) were responsible for the state of one’s personality, and with any physical and psychologic illness an imbalance of these humors could lead to pain. Early medical practitioners continued this quest for relief from pain and suffering with the use of various concoctions including the use of mandrake, one of the earliest known medicinal plants, as a means of inducing analgesia and anesthesia. Crude forms of opium have also been used. The “somniferant” sponge, a sponge saturated with a mixture of opium juices, mandrake root, and other plant extracts, was used for pain relief and in everyday medical treatments, and as a crude anesthetic for the inevitable and almost always painful surgical procedures.23
The history of our understanding of pain physiology and treatments evolved in parallel (to some extent) with general advancements in the field of medicine. During the European Dark Ages (400 to 1300 AD), a time of little progress in any field of science, Middle Eastern medicine and the treatment of pain flourished. For example, the writings of Turkish surgeon Sabuncuoğlu eloquently described procedures involving “cauterization” for the treatment of migraine headaches, dental pain, low back pain, and “sciatica.”102
The nineteenth and twentieth centuries included important advances in pharmacologic treatment for pain. Before this, crude forms of analgesia included the use of laudanum, a mixture of opium, alcohol, and other ingredients given with whiskey or other types of alcohol, for analgesia and also before surgical procedures. Serturner isolated morphine from opium in 1806, leading to advancement in isolation techniques and the subsequent production of morphine (in the 1820s), codeine (in 1832), and synthetic opioids such as methadone and fentanyl (in the 1940s). The chemist Felix Hoffman developed acetylsalicylic acid (aspirin) from extracts of willow tree bark as the first reliable analgesic for the relief of moderate pain.56 Alexander Wood’s development of the syringe made parenteral administration practical and convenient but also led to increased abuse and misuse of the opioids. Diacetylated morphine (heroin) was later introduced by the Bayer Company in 1898 as a cough suppressant.123 Abusers soon learned that the compound could be crushed into a powder and snorted, injected, or smoked with significant euphoric effects. The Harrison Narcotic Control Act was passed in 1914, limiting the use of morphine and other opiates to the care of a physician. Controversies related to the use of opioid medications for ongoing treatment of chronic nonmalignant and cancer-related pain have been a primary focus of federal regulatory and legislative scrutiny. Fear of iatrogenic addiction in the use of chronic opioid management, as well as variability between federal, state, and community-based laws, has led to ongoing physician fears for aggressive management of pain-related conditions. It remains an important evolving contemporary issue related to the treatment of chronic pain.
Many of the advancements in anesthesiology pain management developed from experiences in treating injured soldiers. Twentieth century surgical advancements included the works of René Leriche and his experience with treating wounded World War I soldiers. He eloquently described chronic pain states including phantom limb pain. His work also included descriptions of “sympathetic pain” arising from smooth muscle in peripheral blood vessels. Leriche championed surgical procedures directed at relieving sympathetic-mediated pain, with aggressive surgical procedures involving sympathetic ganglia and surgical “periarterial” sympathectomies. Another surgeon, William K. Beecher, helped to put forward the importance of psychologic factors in the experience of pain. As a young army physician in World War II, he observed significantly less pain reported and fewer requests for pain medication by soldiers severely wounded in battle compared with civilian patients in his practice with similar injuries.20 He went on to describe the “power of placebo,” underscoring the importance of meaning and distraction as important factors in the experience of pain.
The success of the gate control theory in the 1960s helped initiate pain management as a formal field of study. John Bonica formalized the idea of pain management as a multidisciplinary collaboration in the late 1940s. In 1974, Bonica organized a scientific meeting of leaders in the field of pain medicine, which established the IASP. The publication of the IASP’s journal, Pain, occurred 1 year later. The IASP created the first Taxonomy of Pain in 1979 and continues to publish clinical updates and guidelines regarding a number of pain-related conditions (i.e., headache, cancer pain, chronic nonmalignant pain, and complex regional pain syndrome). It also cultivates research related to further understanding of pain mechanisms and treatment developments. A number of agencies and professional societies remain active in the field of pain science and treatment, including the American Pain Society, American Academy of Pain Medicine, and multispecialty spine intervention-based societies such as the North American Spine Society and International Spinal Injection Society. In the past 2 decades, there has been an explosive growth of modern neuroscience that has led to advancement in understanding pain mechanisms and treatment. This is due in part to the financial impetus from the analgesic area, as well as the development of new tools such as functional imaging studies (positron emission tomography and functional magnetic resonance imaging), which have helped to demonstrate evidence of complex cortical networks related to pain perception.236,239
Recently the number of physiatrists becoming interested in pain medicine as a subspecialty has exponentially increased, with many pursuing formal fellowship training. Subspecialty certification in pain medicine is now offered by the American Board of Physical Medicine and Rehabilitation in cooperation with the American Board of Psychiatry and Neurology and the American Board of Anesthesiology. With the growing availability of pain fellowships and the increasing number of physiatrists specializing solely in pain medicine, advanced interventional pain management procedures (including fluoroscopically guided spinal interventions and placement of implantable pain devices) are increasingly being performed by physiatrists as part of a comprehensive treatment plan for chronic pain disorders (see Chapter 25).
Early History of Pain Theory: A Peripheral Perspective
The dualistic or mind–body controversy started with René Descartes’ (1596 to 1650) biomedical theories 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.199
The specificity theory remained somewhat unchallenged until the nineteenth century, with the emergence of physiology as a more formal scientific field of study. Magendie (1783 to 1855) and his student, Claude Bernard (1813 to 1878), revolutionized the field of physiology by codifying the principles of observation, data recording, and analysis (considered heretic at the time!). Bernard 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 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). Müller’s concept included the distinction of four major cutaneous modalities (i.e., touch, warmth, cold, and pain), each with its own projection system to the brain.199
Max von Frey expanded Müller’s idea of specific nerve energies to include a theory based on specific receptors. Von Frey proposed the presence of cutaneous sensitivity maps on the skin “mapped out” by anatomists of the day with a brand new experimental device, the microscope. First, a spotlike distribution of warmth and cold cutaneous sensitivity was mapped out with two devices: a pin on a string, to gauge pressure thresholds for pain, and snippets of horsetail hairs attached to a piece of wood, to map out distributions of “touch spots.” More formal standardized versions of these instruments continue to be used in contemporary sensory testing (i.e., von Frey filaments and von Frey hairs, respectively). Second, von Frey included his theory, later disproved, that there were specific pain receptors (free nerve endings) that varied in their distribution on the body to complement other specialized receptors identified around the same time (Meissner corpuscles, touch; Krause end bulbs, cold; and Ruffini end organs, warmth). Sherrington272 later postulated the existence of specialized cells or “nociceptors,” which could detect noxious sensations in terms of the lowest “lumen” or threshold.
An alternative to these specificity theories, the intensive (summation) theory, was formulated by Erb in 1874. Intensive theory proposed that each sensory transducer was capable of producing pain only if the stimulus reached a sufficient intensity.27 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. William Livingston’s work 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.164 Livingston’s summation theory 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.158
Although debate continued among three basic pain theories, specificity ultimately prevailed and was universally accepted and practiced. An appreciation for cognitive and psychologic 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 psychologic and physiologic processes influenced by past experiences, the environment, and emotional state.119
Melzack and Wall’s gate control theory 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 encephalogenic interneurons that inhibit cephalad transmission in small unmyelinated primary afferent nociceptive fibers and the secondary transmission cells in the lateral spinothalamic tracts.202 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.”
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.254 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 psychologic 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.6 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 42-2). 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.138
History of Contemporary Advancements in Psychologic 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 psychologic 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.105 Physicians such as George Engel (1959) challenged the biomedical model of disease as inadequate, in that it failed to include the social, psychologic, and behavioral dimensions of illness. Engel’s classic article “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.”286 Wilbert Fordyce later proposed an operant conditioning model of chronic pain based on an ends approach of identifying and treating pain behaviors. More contemporaneously, 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.302 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, biologic factors can initiate a physical disturbance, but psychosocial factors often influence pain perception, pain behavior, and the ongoing pain experience.86,301
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 42-3).
| 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 brain stem, 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,328 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 |
Transduction
The principal receptors for pain are the branched endings of C and Aδ fibers (Table 42-4) 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 B4 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.39,64,329 The other class, isolectin B4 binding, contains few neuropeptides but expresses a surface carbohydrate group selectivity binding to the plant lectin isolectin B4 and is supported by glial-derived neurotrophic factor.290 Isolectin B4 expresses P2X3 receptors, a subtype of ATP-gated ion channels.144 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.169
Aδ nociceptors (also responders to noxious, thermal, and chemical stimuli) are most easily classified on functional grounds. Type 2 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 (>50° C). Type 1 Aδ and nociceptive C fibers are more commonly associated with persistent painful sensations.44
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 42-4). 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.46,106,265
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.258 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 (>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).57 Aβ fibers transmit innocuous, mechanical stimuli to deeper laminae (III through 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 42-3). 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.179 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.179
Central Sensitization
The term central sensitization describes a complex set of activation-dependent posttranslational changes occurring at the dorsal horn, brain stem, 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 above). 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).175 Posttranslational changes also include phosphorylation of NMDA and AMPA receptors, activation of second messengers such as nitric oxide, and central prostaglandin production.328
Ascending and Descending Modulation
Melzack and Casey’s classic descriptions of neuroanatomic pathways make a distinction between the lateral and medial pain systems corresponding to their relationship with the thalamus.201 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.323
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.219 Animal and human studies have identified the anterior cingulated cortex in regulating avoidance behaviors and the perception of pain unpleasantness.155 Only a small portion 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 brain stem. Of course, with prolonged pathology 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.151, 327 Besides descending inhibition from cortical areas, recent studies have suggested that descending facilitatory pathways might link brain stem and spinal cord areas via pronociceptive serotonergic281 and opioid mechanisms.79 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.235
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.239 Activation of somatosensory cortices (S1–S2) provides information regarding the quality and intensity of pain.124 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.243 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.289 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.
Psychologic Issues Related to Chronic Pain
The physiatric approach to chronic pain conditions must include an understanding of the wide array of important psychologic (affective and cognitive) factors that impact the multidimensional experience of pain. Psychologic 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 (Figure 42-4).
FIGURE 42-4 Factors associated with adjustment to pain.
(Modified from Keefe FJ, Rumble ME, Scipio CD, et al: Psychological aspects of persistent pain: current state of the science, J Pain 5:195–211, 2004, with permission.)
Affective Factors
Depression
A strong association between chronic pain and depression has been suggested.106,249,291 The prevalence estimates of major depression in patients with chronic pain conditions vary from 5% to 87%, and this variation could be due to a number of analytic factors, including the diagnostic criteria used, type of pain studied, and selection bias.9,83,99 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 chronic pain patients can be higher than with other chronic medical conditions.14 The presence of chronic pain might be related to longer durations of depressive symptoms.75,220 In general, most systematic reviews on the relationship between pain and depression suggest that chronic pain precedes depression.82 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. Depressed patients 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.148,156 Brown et al.32 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,32 underscoring the importance of the complex relationship between 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 below), which serve to promote ongoing pain, physical deconditioning, and social isolation.117 Anxiety as a psychologic construct in chronic pain has been developed by McCracken et al.188 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.188
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.3,131 In a study of patients presenting for chronic pain management, Okifuji et al.221 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.”276 Anger as a construct has also been considered to be related to personality dispositions associated with unconscious conflicts,93 or as a reaction to the presence of ongoing unrelieved pain.78 Others have suggested that chronic pain might develop as a conversion-like symptom to suppress feelings of anger, and suppressed anger could be related negatively to adjustment to ongoing chronic pain.149 In contrast, “anger out” has also been linked to poor adjustment.35 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.”279 Burns35 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.,85,87 who showed that patients with chronic low back pain exhibited greater stress-induced increases in electromyogram readings in lower paraspinal muscles compared with normal subjects. 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.107,293 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.29
Learning Factors
Operant Learning
Fordyce’s operant conditioning approach to pain serves as one of the earliest psychologic models for chronic pain.88 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.163,314 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.315 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 psychologic distress.315
Respondent Learning
The development of chronic pain can also be initiated and maintained by classical or respondent learning. In this case, an aversive stimulus is paired with a neutral stimulus and, with repeated exposures over time, the neutral stimulus will come to elicit an aversive response (i.e., fear). For example, a work-related lifting injury elicits an automatic response such as increased muscle tension and sympathetic arousal (fear and anxiety). Over time, fear and anxiety become associated with the once neutral stimuli of simple work-related activities, and lead to increased avoidance of the behavior.313 With chronic pain, the patient learns to anticipate negative consequences of activity, even in the absence of the noxious stimulus.
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.154 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 chronic low back pain patients. In this way, increased levels of fear and disability can occur independently of the experienced pain intensity.312 McCracken et al.190 found that increased fear and anxiety in low back pain subjects 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.193 In a Dutch study of patients presenting to a primary care clinic with chronic low back pain, approximately 70% of participants agreed to the statement “Simply being careful not to make unnecessary movements is the safest thing I can do to prevent back pain,” and approximately 50% endorsed the statement “Back pain always means that the body is injured.” In addition, patients who reported pain-related fear had increased risk for disability at 6 months (odds ratio = 4.6, 95% confidence interval).230
A cognitive behavioral model emphasizes two opposing behavioral responses: confrontation and avoidance. Waddell et al.’s conclusion that “fear of pain and what we do about pain can be more disabling than pain itself”316 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,88 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).146 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.55 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.185 Operant behavioral therapy approaches can be delivered in individual sessions and in group settings. Operant behavioral therapy techniques that patients can master and apply include pacing and graded exercise, scheduling and/or limiting pain medications and passive treatments, and 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.17 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.318 Five primary assumptions underlie all cognitive behavioral therapy interventions (Box 42-1).28 Cognitive behavioral therapy is a flexible, viable, and empirically validated approach for effectively treating patients with persistent pain.55,211
BOX 42-1 Five Primary Assumptions That Underlie All Cognitive Behavioral Therapy Interventions
From Bradley LA, McKendree-Smith NL, Cianfrini LR: Cognitive-behavioral therapy interventions for pain associated with chronic illness, Semin Pain Med 1:44-54, 2003, with permission.
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.252
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 stages of sleep are stage 1 (light sleep), stage 2, stage 3, stage 4 (deep or delta-wave sleep), and REM sleep. Stage 1 is a transitional stage between wakefulness and sleep. It comprises 2% to 5% of total sleep time and occurs when initially falling asleep and during brief arousal periods within sleep. Stage 2 is marked by sleep spindles and K complexes and occurs throughout the sleep period, accounting for 45% to 55% of total sleep time. NREM stages 3 and 4 occur primarily during the first third of sleep and are commonly referred to as delta-wave, slow-wave, or deep sleep. They account for approximately 20% of total sleep time. REM sleep is characterized by fast electroencephalograph activity, skeletal muscle atonia, REM, and bursts of autonomic activity. The last third of sleep is primarily spent in REM.252
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.252,256 The ventrolateral preoptic nucleus has been shown to contain GABAergic and galaninergic neurons that are necessary for normal sleep.263 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.170 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 elderly persons compared with young adults.256
The interrelationship between disturbed sleep and chronic pain conditions is well documented for both adults and adolescents.208,209,226,231,278 Prevalence estimates of disturbed sleep range from approximately 50% to 90% depending on the clinical study population under evaluation.38,208,209 Although the nature of the relationship between pain and disturbed sleep is not well understood, a reciprocal association is suggested.2,278 Current research suggests a multifactorial relationship including depression, fear-avoidance behaviors, catastrophizing, and even treatments such as benzodiazepines and chronic opioid therapy.174 Patients with chronic pain can display frequent sleep fragmentation, longer sleep latency, and decreased overall quality of sleep.37 Sleep fragmentation is characterized by repetitive short interruptions in sleep and is a recognized factor in the cause of excessive daytime sleepiness.284 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. In fact, a study of 679 subjects with chronic widespread pain (CWP) found that although rapid onset of sleep, absence of early awakening, and restorative sleep were associated with the resolution of CWP, after adjusting for the effects of psychosocial factors, restorative sleep was independently associated with the resolution of chronic widespread pain.63
