Pain Part 1

Definitions and Overview

The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage."1 Although pain most often has a proximate physical cause, the current definition avoids tying pain directly to a stimulus, because pain of probable psychological origin may be reported in the absence of actual tissue damage or any other likely pathophysiologic cause.

Pain is not simply the unidirectional transmission of data along hardwired tracts from peripheral tissue to the central nervous system.2 Indeed, pain is experienced within a complex biologic, emotional, psychological, and social context that may defy physical examination findings, diagnostic procedures, and laboratory tests.

Pain may be considered to consist of four broad components: nociception, perception, suffering, and behaviors.3 Nociception is the detection of tissue damage by specialized receptors (nociceptors) on A-delta fibers and C fibers. This is a dynamic process in which the action of nociceptors is influenced by the local chemical environment and by neural changes set into motion by local tissue damage.4 Perception of pain, although often triggered by local injury, may also result from lesions in the peripheral nervous system or the CNS; pain may thus be perceived in the absence of nociception. The intensity of pain may have little or no relation to the extent of objective pathology. Suffering may be defined as the state of severe distress associated with events that threaten the intactness of the person.5 Suffering can include physical pain but is not limited to it. Pain behaviors are observable, quantifiable behaviors arising from pain and suffering; such behaviors include restricting activity, verbally complaining of pain, or seeking health care.


There are several different types of pain, with differing mechanisms, temporal courses, and management options. Transient pain results from the activation of nociceptors in the absence of tissue damage; it is not a clinically significant cause of health care utilization. Acute pain is marked by an extensive nociceptive and behavioral cascade triggered by local tissue damage. It is a normal physiologic response to adverse chemical, mechanical, or thermal stimuli. Although acute pain is not defined by time course, it will generally subside within weeks. Chronic pain most often occurs when an initial injury exceeds the body’s capacity for healing or involves the nervous system itself. Pain is defined as chronic rather than acute not on the basis of its duration, per se, but on the basis of the body’s inability to restore physiologic function to homeostatic levels. The intensity of chronic pain may bear little relation to initial tissue damage or subsequent quantifiable pathology; indeed, a number of chronic pain syndromes lack any identifiable tissue damage or trigger injury.

The complexity of pain physiology may lead to suboptimal pain assessment and management, as occurs when patient complaints are not believed because of a lack of objective data or when clinicians lack an understanding of pain physiology. Surveys of physicians and medical students have repeatedly confirmed the need for improved education and training in pain recognition and treatment.7 Provider surveys reveal that many practitioners do not feel comfortable with pain management. One large study found that 86% of physicians believed that most of their patients with pain were undertreated, whereas only 51% felt pain control in their practices was "good" or "very good."8 A model of care that is oriented toward diseases rather than symptoms may incorrectly minimize the therapeutic importance of symptom management. In addition, attitudes of both physicians and patients toward opioids and the fear of patient addiction contribute to the inadequate treatment of pain associated with cancer and a variety of other chronic conditions.9

Epidemiology

Acute pain is the most common symptom for which patients seek medical evaluation.10 New pain complaints result in 40 million visits to the doctor annually, and 45% of persons in the United States will visit a doctor for pain at some point in their lives.11 The prevalence of various chronic pain syndromes in the United States is estimated to range from 2% to 40%.12 Approximately 75 million persons in the United States live with "serious pain," and nearly 50 million are partially or totally disabled by pain.13 In addition, recurrent acute pain is a prominent feature of a number of diseases, such as sickle cell anemia, AIDS, and malignancy. The prevalence of pain in cancer patients is estimated to range from 14% to 100%, with pain more frequent in advanced disease and certain types of malignancy.14 Estimates of the prevalence of pain in AIDS patients vary from 30% to 90%; in one study, ambulatory AIDS patients experienced two to three concurrent pains.15 The Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment (SUPPORT) found that approximately 50% of adults who die in hospitals experience moderate to severe pain in the period immediately before death.16

The financial costs of pain, especially untreated pain, to society are significant—approximately $100 billion annually in the United States.17 The American Productivity Audit estimates that losses in productivity because of common painful conditions in active workers costs the economy $61.2 billion annually, with the majority of this cost related to reduced performance while at work rather than absence from the job.18 One study found that 13% of the total workforce experienced a loss in productive time during a 2-week period because of a common pain condition. The cost of chronic back pain alone has been estimated to be $28 billion per year.19 In addition, pain results in 50 million lost work days a year in the United States. Both acute and chronic pain are significant drivers of increased utilization of health care resources. Persons with chronic pain are five times as likely as those without chronic pain to use health care services.

Neurobiology of Pain

Peripheral pain

Nociception

Nociception is the reception of signals in the CNS evoked by the activation of specialized sensory receptors (nociceptors) that provide information about tissue damage [see Figure 1 ]. Nocicep-tors are the free peripheral endings of primary sensory neurons;the cell bodies of nociceptors are located in the dorsal root and trigeminal ganglia. Nociceptors are the least differentiated of cutaneous sensory receptors; unlike other somatic sensory receptors, they lack the structures for filtering peripheral stimuli.

Different classes of nociceptive afferent fibers react to different types of stimuli. A-delta fibers function as thermal and high-threshold mechanical receptors. Activation of these fibers generally results in short sensations of sharp, pricking pain. A-delta fibers are of small diameter and are thinly myelinated; they conduct impulses at the relatively fast rate of 5 to 30 m/sec. They terminate in laminae I and V of the dorsal horn. C fibers function as polymodal receptors and are activated by various high-intensity mechanical or chemical stimuli, as well as by hot (> 45° C) or cold stimuli. Activation of C fibers results in more prolonged sensations of dull pain. C fibers are small in diameter; they are unmyelinated and conduct impulses at the slow rate of 0.5 to 2 m/sec. C fibers have smaller receptive fields than the A-delta nociceptors. They terminate in lamina II. Polymodal C fibers compose a large majority of peripheral nociceptors. The cell bodies of both A-delta fibers and C fibers reside in the dorsal root ganglion. Some nociceptors, which are termed silent or sleeping, have such a high activation threshold that under normal circumstances they do not react to most stimuli; they are recruited under conditions of inflammation and tissue damage (see below). All classes of nociceptive fibers are widely distributed throughout cutaneous and deeper tissue.

Nociceptors do not fire spontaneously at rest. Their electrical action potential is triggered by transduction, which occurs when a noxious stimulus of sufficient strength depolarizes the nocicep-tor membrane. The specific receptive properties of nociceptors are determined by their expression of transducing ion-channel receptors. These ion channels are nonselective potassium or sodium channels gated by temperature, chemical stimuli, or mechanical shearing forces rather than by voltage. Activation of the channels by an appropriate stimulus leads to an inward current that depolarizes the receptor membrane. If this depolarizing current is sufficient to activate voltage-gated sodium channels, further depolarization of the membrane will occur, and a burst of action potentials will be initiated. The duration and frequency of this burst are determined by the duration and intensity of the noxious stimulus. Many, but not all, of these transducing receptors have been identified.

The typical noxious stimulus affects some combination of the different types of nociceptors in a given area of tissue damage. A-delta fibers provide sensory input for immediate, sharp pain, whereas C fibers are responsible for delayed, dull pain. The summation of input from both types of nociceptors provides the sensory basis for the perception of pain.

Peripheral Sensitization

The nociceptive process occurs in the context of a number of changes in the chemical environment brought about by local tissue damage and the release of a variety of inflammatory mediators. Some of these mediators act to enhance the sensation of pain in response to subsequent stimuli in the affected area by decreasing nociceptor stimulus thresholds and increasing and prolonging receptor firing and intensity in response to a supra-threshold stimulus, a process called peripheral sensitization.20-22 Prostaglandin E2, released from arachidonic acid-damaged cells, binds to G protein-coupled prostaglandin E receptors to sensitize nociceptors. Interleukin-lb and tumor necrosis factor-a, released by immune system cells involved in the inflammatory response, induce the release of cyclooxygenase-2 (COX-2) several hours after the start of inflammation. COX-2 converts arachidonic acid to prostaglandin H, which is subsequently converted into prostanoid species, including prostaglandin E2. Bradykinin, a peptide derived from plasma kininogen, sensitizes primary afferent neurons via its constitutive B2 receptor. Nerve growth factor sensitizes nociceptor terminals by binding to the G protein-coupled tyrosine kinase A receptor. Leukotrienes derived from arachidonic acid-damaged cells also alter the sensitivity of nociceptor terminals. Certain peptides released by primary afferent neurons themselves support the process of peripheral sensitization. Substance P, released from activated nociceptors, acts on local mast cells to increase histamine release.

Peripheral sensitization is thought to be one of the processes underlying the phenomenon of primary hyperalgesia, whereby injury to peripheral tissues results in an enhanced sensation of pain in response to subsequent suprathreshold stimuli in the damaged area. Experimental evidence supports the ability of heat stimuli to yield primary hyperalgesia; data concerning mechanical stimuli are not as clear. The evolutionary purpose of hy-peralgesia is to discourage further contact with damaged tissue, thereby expediting the healing process. Peripheral sensitization and the consequent hyperalgesia normally resolve as tissue heals. However, chronic pain (see below) may occur if the body is unable to restore homeostasis because the initial injury has exceeded the body’s capacity for recovery or the injury involves the nervous system itself. Secondary hyperalgesia—the expansion of hyperalgesia beyond the region of initial tissue damage in the absence of ongoing or recurrent injury—is caused by additional nervous system changes secondary to the initial insult [see Central Sensitization, below].

Dorsal horn physiology

Nociceptive fibers bifurcate upon entering the spinal cord laterally in the dorsal root, with branches of each axon ascending and descending for several segments in the tract of Lissauer. A-delta and C fibers terminate mainly in lamina I (marginal zone) and lamina II (substantia gelatinosa) of the dorsal horn [see Figure 2]. In addition, some A-delta fibers terminate in lamina V.

The primary afferent fibers communicate directly or indirectly with two major classes of neurons in the dorsal horn: projection neurons and local circuit interneurons. Projection neurons are contacted directly by A-delta fibers and relay sensory data to the brain stem, hypothalamus, and thalamus. They stretch the length of the spinal cord, with cell bodies in laminae I and V of the dorsal horn. Nociceptive-specific (NS) projection neurons relay data solely from A-delta and C fibers, whereas wide-dynamic-range (WDR) projection neurons relay both noxious data from nociceptors and a variety of innocuous stimuli from low-threshold mechanoreceptors. Both NS and WDR neurons are important in the relaying of nociceptive information; NS data signal the presence of possible tissue damage, whereas WDR data concern stimulus quality and, possibly, location. Local circuit in-terneurons modify the output of projection neurons. Excitatory interneurons relay sensory input from C fibers to projection neurons; inhibitory interneurons regulate and suppress the flow of nociceptive data to higher centers.

The relaying of nociceptive data in the dorsal horn involves several different neurotransmitters. Both A-delta and C fibers release glutamate, an excitatory amino acid that is the major fast excitatory neurotransmitter for all nociceptive modalities. Gluta-mate acts at two major classes of glutamate receptors on secondary afferent neurons: ionotropic and metabotrophic. Iono-tropic glutamate receptors, which include the receptors for N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA), and kainite, mediate fast syn-aptic transmission, the rapid depolarization of the secondary afferent neuron membrane. This depolarization will generate an action potential if the threshold is met. Metabotrophic glutamate receptors are coupled to a variety of intracellular second messenger systems via G proteins. These receptors are expressed pre-synaptically and postsynaptically in the dorsal horn and throughout the neuraxis, and they play a role in the modulation of pain. The presynaptic receptors on the central terminals of no-ciceptors may alter neurotransmitter release; they are a major target of analgesic therapies.

In addition to glutamate, nociceptive afferents (primarily C fibers) release a large variety of neuropeptides, including substance P, calcitonin gene-related peptide, cholecystokinin, somatostatin, galanin, gastrin-releasing peptide, and substance K. The neuropeptides act on G protein-coupled receptors and are responsible for evoking slow excitatory postsynaptic potentials in the secondary afferent neurons of the dorsal horn.

Initial modulation of the transmission of pain data from the periphery to higher centers occurs in the dorsal horn. Secondary afferent neurons of the dorsal horn are involved in the determination of which action potentials trigger reflex action to avoid further injury from noxious stimuli, as well as which action potentials are transmitted to the brain. Inhibitory interneurons release the neurotransmitter y-aminobutyric acid (GABA), which acts at receptors on secondary afferent neurons to produce inhibitory postsynaptic action potentials, modulating the transmission of excitatory action potentials received from primary affer-ents. A major role of the dorsal horn is to suppress pain. Most sensory information relayed to the secondary afferent neurons of the dorsal horn does not evoke an action potential.

(a) Stimulation of C fibers by intradermal injection of capsaicin or thermal injury produces spontaneous pain and pain evoked by light touch at the site of injury (primary hyperalgesia). In addition, an area of secondary hyperalgesia (increased pain after a noxious stimulus) outside of the area of primary injury is produced by the activation of N-methyl-d-aspartate (NMDA) receptors in the central nervous system, which occurs as a consequence of the afferent nociceptive impulse traffic. (b) When activated by mechanical, thermal, and chemical stimuli, nociceptors conduct afferent impulses toward the spinal cord. (c) When areas in the thalamus and cerebral cortex are activated, secondary projections in the spinothalamic tract, dorsal column tract, and other nociceptive pathways lead to the conscious perception of pain.

Figure 1 (a) Stimulation of C fibers by intradermal injection of capsaicin or thermal injury produces spontaneous pain and pain evoked by light touch at the site of injury (primary hyperalgesia). In addition, an area of secondary hyperalgesia (increased pain after a noxious stimulus) outside of the area of primary injury is produced by the activation of N-methyl-d-aspartate (NMDA) receptors in the central nervous system, which occurs as a consequence of the afferent nociceptive impulse traffic. (b) When activated by mechanical, thermal, and chemical stimuli, nociceptors conduct afferent impulses toward the spinal cord. (c) When areas in the thalamus and cerebral cortex are activated, secondary projections in the spinothalamic tract, dorsal column tract, and other nociceptive pathways lead to the conscious perception of pain.

Upon entering the spinal cord laterally in the dorsal root, A-delta fibers and C fibers terminate mainly in lamina I (marginal zone) and lamina II (substantia gelatinosa) of the dorsal horn. In addition, some A-delta fibers terminate in lamina V. Secondary afferent neurons of the dorsal horn are involved in determination of which action potentials trigger a reflex response to avoid further injury from noxious stimuli, as well as which action potentials are transmitted to the brain. A major role of the dorsal horn is to suppress pain. Most sensory information relayed to the secondary afferent neurons of the dorsal horn does not evoke an action potential.

Figure 2 Upon entering the spinal cord laterally in the dorsal root, A-delta fibers and C fibers terminate mainly in lamina I (marginal zone) and lamina II (substantia gelatinosa) of the dorsal horn. In addition, some A-delta fibers terminate in lamina V. Secondary afferent neurons of the dorsal horn are involved in determination of which action potentials trigger a reflex response to avoid further injury from noxious stimuli, as well as which action potentials are transmitted to the brain. A major role of the dorsal horn is to suppress pain. Most sensory information relayed to the secondary afferent neurons of the dorsal horn does not evoke an action potential.

Gate control theory

The gate control theory of pain, originally described by Mel-zack and Wall in 1965, posits that input from large-diameter primary afferent fibers in the peripheral nervous system activate inhibitory interneurons in the substantia gelatinosa (lamina II of the dorsal horn).23 Activation of these inhibitory interneurons, in turn, reduces the effectiveness of nociceptive input from small-diameter primary afferent fibers in activating projection neurons of the spinothalamic, spinoreticular, or spinomesencephalic tracts.

Thus, large-diameter input "controls the gate" by which small-diameter input transmits data on noxious stimuli to higher pain centers. This concept is the theoretical basis for the inhibition of pain by rubbing or vibration, as well as therapeutic modalities such as transcutaneous electrical nerve stimulation (TENS).24

Central sensitization

Central sensitization is a pathologic state in which dorsal horn excitability is increased and gatekeeping function is lost.2-"7 This facilitated responsiveness to sensory input leads to primary hyperalgesia (as is seen in peripheral sensitization). It also leads to secondary hyperalgesia, in which an exaggerated response to noxious stimuli is observed beyond the region of actual tissue damage. Allodynia, in which pain is generated by a low-intensity stimulus that would not be noxious to normal tissue, is also seen.

The pathogenesis of central sensitization may be thought of as occurring in two phases. The first stage is triggered by intense nociceptive input to the secondary afferent neurons of the dorsal horn and may thus be considered activity dependent. This excessive input may arise from persistent acute injury, surgical insult, peripheral sensitization of nociceptors during inflammation, ectopic discharge from nerve injury, a variety of chronic pain syndromes, or certain other conditions. The activity-dependent stage of central sensitization occurs rapidly; hyperresponsive-ness of spinal neurons may be seen within seconds of massive sensory input triggered by an appropriate initial insult.

NMDA receptors on secondary afferent neurons of the dorsal horn are of critical importance in the pathology of central sensiti-zation. Under normal conditions, glutamate does not have activity at the NMDA receptor during nociception. This is because the receptor has a voltage-dependent magnesium ion block on its calcium channel; glutamate is rapidly cleared from the synap-tic cleft, and the neuron is not depolarized long enough to allow the magnesium ion block to be dislodged. However, excessive frequency of nociceptive input—primarily, temporally summat-ed slow excitatory postsynaptic potentials from C fibers—lead to a persistent net increase in the amount of glutamate in the synaptic cleft and depolarization of secondary afferent neurons of sufficient duration to dislodge the magnesium ion block. The resultant activation of NMDA receptors by glutamate leads to a number of signaling cascades initiated by increased intracellular calcium influx, including G protein-coupled neurokinin receptors and receptor tyrosine kinases, as well as phosphokinases.28 Activation of protein kinases leads to phosphorylation of the NMDA receptor ion channels, decreasing the magnesium block at resting membrane potentials and prolonging channel opening time. As a result, sensitized secondary afferent neurons respond more easily to continued signals from C fibers; in addition, spontaneous or ectopic signal discharge may occur in the context of loss of gatekeeping function.

Central sensitization is mediated by both postsynaptic (see above) and presynaptic NMDA receptors in the dorsal horn. Many small-diameter primary afferent fibers synapsing in the dorsal horn express NMDA receptors. Glutamate released from the presynaptic terminal may use these receptors to enhance its own release in a feed-forward mechanism in response to subsequent stimuli. Presynaptic NMDA receptors can facilitate the transmission of nociceptive messages secondary to the release of substance P, calcitonin gene-related peptide, and glutamate from primary afferent terminals.

The second stage of central sensitization is sustained beyond the initial insult by transcriptional changes in the cell and may be considered transcription dependent. Two basic types of transcriptional change occur. One type is restricted to parts of the nervous system receiving sensory input from injured tissue; this process is activity driven. The other type of transcriptional change is widespread and produces a variety of functional effects. Induction of COX-2 in the central nervous system after peripheral inflammation is an example of this process; widespread production of COX-2 leads to a diffuse increase in prostaglandin E2, with consequent diffusely increased neuronal excitability.

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