CHAPTER 11: Pain

• Nociception is the form of somatic sensation that detects noxious, potentially tissue-damaging stimuli. Pain has both a localizing somatic sensory component and an aversive emotional and motivational component.

• Pain begins with peripheral nociceptors, which have their cell bodies in dorsal root ganglia (DRG) and in the trigeminal ganglia in the head; these neurons synapse, respectively, in the dorsal horn of the spinal cord or the trigeminal nucleus, the medullary extension of the dorsal horn.

• Peripheral nociceptors express a set of channels, most notably transient receptor potential (TRP) channels, that are sensitive to noxious mechanical, thermal, and chemical stimuli. These neurons also express receptors for inflammatory mediators and substances released by damaged cells.

• Primary nociceptors release a large number of neuropeptide and nonpeptide neurotransmitters in the dorsal horn and trigeminal nucleus. These regions are important sites of integration for both ascending nociceptive information and descending antinociceptive (endogenous analgesic) influences.

• Sensitization is a clinically significant process in which nociceptors in an area extending beyond a tissue injury exhibit decreased thresholds for activation. Sensitization can be initiated by inflammatory mediators such as prostaglandins and leukotrienes.

• Damage to neurons in nociceptive pathways can lead to severe chronic pain syndromes, termed neuropathic pain.

• Plasticity within the dorsal horn and trigeminal nucleus, termed central sensitization, may be key in the initiation of chronic pain syndromes by increasing the excitability of neurons in nociceptive pathways. Numerous mechanisms have been implicated in central sensitization, including plasticity mediated by NMDA glutamate receptors.

• Opiate drugs selectively suppress nociception, but not other sensory modalities, by binding to endogenous opioid receptors in descending analgesic pathways. They are the most potent analgesic compounds known, but their chronic use is limited by tolerance to their analgesic effects and by risk for addiction.

• Nonsteroidal anti-inflammatory drugs (NSAIDs), which are more weakly analgesic compared with opiates, act by blocking prostaglandin-mediated sensitization, specifically by inhibiting the enzyme cyclooxygenase that is required for the synthesis of prostaglandins from arachidonic acid.

• Several other medications are used to treat chronic pain syndromes, including combined serotonin–norepinephrine reuptake inhibitor (SNRI) antidepressants and compounds (eg, gabapentin, pregabalin) that inhibit certain voltage-gated Ca²⁺ channels.

Chronic pain is a significant public health problem associated with severe patient suffering and disability and, in some cases, drug abuse. Pain begins, however, as an adaptive response to actual or potential harm to the body with the stimulation of peripheral nociceptors, neurons specialized to detect noxious stimuli. Pain is not simply a modality of somatic sensation such as touch or vibration sense, however. Pain also has physiologic, behavioral, and aversive emotional components. Without its alerting and aversive components, its activation of withdrawal reflexes and avoidance behaviors, or its capacity to inscribe powerful emotional memories, pain would not reliably trigger escape from danger and avoidance of future harm 11–1. When it becomes chronic, however, pain loses its adaptive role as a defender of the body’s tissues and instead becomes a pressing medical problem. The aversive emotions associated with pain no longer serve a protective function, but rather produce suffering and, all too often, maladaptive behaviors. Chronic pain may result from continuing tissue damage, as can occur with cancer, but much chronic pain results from chronic inflammatory processes or damage to the pain pathways themselves (eg, by trauma, nerve compression, diabetes, or herpes varicella-zoster infection), in which case it is termed neuropathic pain. Neuropathic pain continues long after tissues have healed, and thus becomes a persistent false alarm.

In sum, pain has both a discriminative sensory aspect and an emotional and motivational aspect. Because of its discriminative sensory component, a person can describe where the pain seems to arise (although, as will be discussed, pain from viscera can seem to come from the body surface) and can delineate its characteristics (eg, sharp, pricking, aching, burning). Because of its emotional and motivational component, pain interrupts ongoing behaviors and demands attention; it also powerfully motivates learning and thereby suppresses behaviors that put an organism in harm’s way. The emotional and motivational component gives pain its survival value, but also can produce suffering and disability when pain is chronic.

Pain begins with primary afferent nociceptors that have cell bodies in dorsal root ganglia (DRG) and that make synapses in the dorsal horn of the spinal cord 11–1. Primary nociceptors in the face and head have their cell bodies in trigeminal ganglia and synapse in the brainstem continuation of the dorsal horn, called the trigeminal nucleus. Throughout this discussion we will use the terms DRG and dorsal horn with the understanding that the same principles apply to their rostral extensions in the head.

The peripheral terminals of primary afferent nociceptors are morphologically undifferentiated free nerve endings. However, these nerve endings express a panoply of receptors and channels 11–2. They express a large number of G protein–coupled receptors, including bradykinin B₂, eicosanoid, purine nucleoside P2Y, histamine, serotonin 5HT₁ and 5HT_2A, γ-aminobutyric acid GABA_B, α₂-adrenergic, somatostatin, neuropeptide Y, and μ, δ, and κ opioid receptors. They also express ligand-gated channels, such as the ATP-gated P2X₃ receptor, and a subset of mature nociceptors express TrkA, the protein tyrosine kinase that binds nerve growth factor (NGF). (All developing nociceptors express TrkA and are dependent on NGF; see 11–1.) In addition, nociceptive terminals express diverse channels involved in transducing noxious signals, including transient receptor potential (TRP) channels 11–1; 11–2, heat-sensitive K⁺ channels, and acid-sensing ion channels (ASICs). These various types of ion channels can be gated directly by noxious heat, cold, mechanical stimulation, acid, or irritant chemicals. Alternatively, TRP channels may be coupled to activation of G protein–coupled receptors, as appears to be the case for the bradykinin B₂ receptor 11–3.

Many of the TRP channels transduce environmental stimuli such as temperature and exogenous chemicals. Many of the G protein–coupled receptors and ligand-gated channels detect tissue damage that causes, for example, release of ATP and of K⁺ and H⁺ ions from damaged cells. In the vicinity of an injury, serotonin is released from platelets, and histamine from tissue mast cells. Bradykinin, one of the most potent activators of nociception, is produced from plasma kininogen by the actions of kallikreins, enzymes that are activated rapidly at the site of an injury 11–3 (see 11–5). However, the interactions of G protein–coupled receptors and of TRP and other channels are complex and an important avenue for research on pain and analgesia.

Because nociceptors are specialized to respond only to noxious stimuli, the channels that transduce environmental signals have high thresholds for activations—in marked contrast to the transducers for light touch 11–3. When activated, noxious stimulus-detecting channels produce inward (depolarizing) currents within the peripheral terminals of primary nociceptors that can initiate trains of action potentials that are then transmitted to the dorsal horn of the spinal cord. Nociceptive neurons of DRG represent “first-order” neurons that synapse on “second-order” neurons within the dorsal horn of the spinal cord (see 11–1). These second-order neurons may be local interneurons or projection neurons that carry nociceptive information to the brainstem and thalamus.

Primary nociceptive neurons must convey signals that distinguish between innocuous and noxious stimuli. Nociceptors accomplish this in one of two ways. They either possess high thresholds for stimulation as noted above or possess the capability of coding the intensity of a stimulus in the frequency of impulses relayed centrally, so that noxious stimuli produce the highest firing rates (see 11–3). A_δ nociceptors, or high-threshold mechanoreceptors, respond to noxious mechanical stimuli, especially sharp objects; approximately half of the mechanothermal nociceptors also respond to noxious thermal stimuli. The majority of C fibers in cutaneous nerves, which are unmyelinated, have higher thresholds than those of myelinated axons, and respond nonselectively to noxious mechanical, thermal, and chemical stimuli. They are therefore known as polymodal nociceptors. Activation of C fibers is mediated by a wide range of endogenous chemicals that are released in response to damaged tissue or inflammation.

Finally, not all receptors and channels expressed on primary nociceptors transmit pain signals. Cannabinoid CB₁ and μ, δ, and κ opioid receptors expressed on nociceptors have been demonstrated to mediate analgesia. Indeed, evidence from genetically engineered mice, with CB₁ receptors deleted only in primary nociceptors, suggests that peripheral CB₁ receptors play a major role in cannabinoid-mediated analgesia. This might permit development of cannabinoid analgesics that do not cross the blood–brain barrier and are thus free of cognitive and psychotropic effects (Chapter 16). Local analgesics and anesthetics take advantage of the presence of opioid receptors and Na⁺ channels, respectively, on the nociceptor terminals to provide temporary relief to specific body regions (see below). Typical routes of administration include topical application or injection in the vicinity of peripheral nerve endings or major nerve trunks.

Peripheral nerves contain several different types of axons that carry sensory information; the greater the diameter and thickness of myelination of the axons, the greater their conduction velocity. The axons of cutaneous afferent nerves belong to one of three main classes. The largest and most heavily myelinated axons that originate from the skin are called A_β fibers. A_α axons, which are thicker, innervate muscles and joints; these axons are involved in proprioception, the transmission of sensory information related to posture, motion, and position. A_β fibers include cutaneous mechanoreceptors, which are free nerve endings that respond to light touch and the bending of hairs. Primary nociceptive neurons have small-caliber axons, some of which are thinly myelinated A_δ axons and most of which are unmyelinated C fibers. Given their lack of myelination, C fibers conduct impulses very slowly (<2 m/s) compared with A_δ fibers (approximately 20 m/s) 11–2; 11–4.

At sites of tissue damage, diffusable mediators, including arachidonic acid metabolites such as prostaglandins and leukotrienes, cytokines such as interleukin-1 (IL-1), chemokines, and growth factors such as NGF, induce a form of neural plasticity within nociceptors called sensitization. The area of sensitized nociceptors usually extends beyond the borders of tissue damage 11–4. Some mediators such as bradykinin 11–3 can both activate and sensitize nociceptors. Typically, sensitization decreases the thresholds for activation of nociceptors. Thus, previously innocuous stimuli, such as light touch, now activate nociceptors and are experienced as painful; this is termed allodynia. Moreover, the response to noxious stimuli is exaggerated, referred to as hyperalgesia. At its most extreme, sensitization might produce pain in the absence of a stimulus (ie, spontaneous pain). Sensitization of C fibers can be measured in humans using the technique of microneurography. Possible mechanisms of sensitization include increased expression and distribution of nonselective cation channels, ectopic nerve activity, and second messenger–dependent phosphorylation of TRP channels and Na⁺ channels in pain pathway neurons in a manner that alters their thresholds for opening.

Heightened sensitivity to previously innocuous stimuli presumably serves the adaptive purpose of leading an organism to protect an injured area in the short term, but it is a major cause of clinically significant pain if it persists. Sensitization of primary nociceptors may lead to sensitization of second-order neurons within the dorsal horn. Changes in the spinal cord include strengthening of synaptic inputs from both nociceptors and low-threshold mechanoreceptors onto nociceptive neurons, both of which contribute to amplification of pain. The recruitment of normally innocuous afferent inputs to the nociceptive pathway is an important aspect of central sensitization. The combination of peripheral and central sensitization underlies neuropathic pain.

Neurogenic inflammation results from the release of peptides from the peripheral terminals of nociceptive neurons into surrounding tissues. This process reflects a bidirection flow of information between the nervous system and immune system. Such “retrograde” release occurs in response to tissue damage, to endogenous inflammatory mediators, or perhaps to exogenous chemicals. Neurogenic inflammation is a normal homeostatic response to inflammation or tissue damage in diverse organs, including skin, joints, gut, bladder, and the respiratory system. When inappropriate or excessive, however, it may contribute to several pathological conditions, possibly including arthritis and asthma.

Peptides released by nerve terminals in neurogenic inflammation are the tachykinins, substance P and neurokinin A, and calcitonin gene–related peptide (CGRP) 11–5. Recall from Chapter 7 that CGRP is generated from the calcitonin gene via alternative splicing. Substance P causes vasodilation and extravasation of plasma proteins from capillaries, which contributes to the generation of bradykinin from kininogen (see 11–3) and release of other proinflammatory mediators such as prostaglandins. In addition, it causes mast cell degranulation with release of histamine. Neurogenic inflammation is attenuated by antagonists of the NK₁ (substance P) receptor and in genetically engineered mice lacking NK₁ receptors. CGRP causes vasodilation and has proprioceptive effects, but its role in extravasation of plasma proteins from blood vessels is unclear.

The cell damage associated with inflammation acts on cell membranes to cause leukocytes to release degradative enzymes. For example, arachidonic acid and various eicosanoids are synthesized from precursor compounds.

Until the early 1980s, the presence, intensity, and duration of pain, whatever its etiology, was thought to simply reflect the degree and timing of nociceptor activation. A noxious stimulus was required to produce pain, but after tissue injury peripheral sensitization could increase the sensitivity of nociceptors in the inflamed region such that they responded to less intense innocuous stimuli, while after nerve injury ectopic activity in nociceptors could generate spontaneous pain. The discovery of central sensitization, a form of long-lasting synaptic plasticity in the dorsal horn triggered by nociceptors that facilitates nociceptive processing, has resulted in a substantial shift in the understanding of the generation of chronic pain syndromes.

Dorsal Horn of the Spinal Cord

The gray matter of the spinal cord is organized as a laminar structure; generally 10 layers are identified 11–6. Laminae I to VI make up the dorsal horn, with lamina VI discernible only in the cervical and lumbar enlargements of the cord. Based on the appearance of freshly cut sections, lamina II often is referred to as the substantia gelatinosa. Primary nociceptive neurons synapse in the dorsal horn of the spinal cord on neurons in laminae I, II, IV, and V. (Axons from the face and head synapse in the trigeminal nucleus in the brainstem as noted earlier.) Within these laminae, the primary nociceptive neurons synapse on both projection neurons, which relay information to the brainstem, hypothalamus, and thalamus, and to local circuit neurons, including both excitatory and inhibitory interneurons. Local circuit neurons not only process afferent information but also convey nociceptive information to the autonomic nervous system and to motor neurons involved in local withdrawal reflexes. Diverse inputs may converge on a single dorsal horn cell. Such inputs include those from descending analgesic pathways, discussed below. Consequently, the dorsal horn is not a simple relay station but an important site of integration for both nociceptive and analgesic information.

The existence of multiple inputs on individual dorsal horn neurons may help to explain the phenomenon of referred pain. Such pain arises in viscera but is experienced as emanating from the body surface. Pain that originates in particular deep structures tends to correspond to the same sites of referred pain in all individuals. The pain of cardiac ischemia, for example, is commonly experienced as running from the chest down the left arm. Likewise, pain that originates in the diaphragm is often referred to the shoulder. These and other types of referred pain are most likely caused by the convergence of axons of visceral and cutaneous nociceptive neurons on the same neurons in the dorsal horn of the spinal cord. When a single neuron in the dorsal horn receives both visceral and cutaneous inputs, higher processing centers of the brain cannot distinguish the source of pain and refer it to the body surface.

Neurotransmitters and Receptors in the Dorsal Horn

Stimulation of afferent A_δ and C fibers evokes fast excitatory postsynaptic potentials in dorsal horn neurons, which appear to be mediated by glutamate, the major neurotransmitter used by DRG neurons. These fast responses to glutamate are mediated by both AMPA and NMDA receptors. Certain projection neurons with cell bodies in the dorsal horn, which are described as nociceptive specific, exhibit high electrophysiologic thresholds. Others, which are referred to as wide dynamic range (WDR) neurons, receive inputs from both nonnociceptive and nociceptive neurons and respond to stimuli of increasing intensity with a corresponding increase in their rate of firing.

High-intensity stimulation or injury to primary nociceptive neurons results in production of additional slow excitatory postsynaptic potentials in dorsal horn neurons, which most likely are caused by the release of various neuropeptides. Primary nociceptive neurons contain a complex array of neuropeptides that can act on spinal cord neurons 11–7. Some of the neurotransmitters, neurotransmitter receptors, and signaling molecules implicated in the synaptic changes underlying activity-dependent central sensitization are the NMDA, AMPA, and mGluR glutamate receptors, the substance P NK₁ receptor, BDNF and its TrkB receptor, ephrinB and its EphB receptor, several protein kinases—for example, CaM-kinase II, protein kinase A, protein kinase C, Src kinase, and ERK, the transcription factor CREB, and the K⁺ channel K_V4. These molecules contribute to the development of synaptic changes including long-term potentiation that then facilitate activity-dependent sensitization. These findings have provided a mechanistic explanation for how low-threshold A and C fibers can begin to produce pain. This plasticity of dorsal horn neurons is believed to be an important factor in the development of persistent pain 11–5.

Multiple Pathways to the Brain

Axons of projection neurons from the dorsal horn cross the midline and ascend into the anterolateral quadrant of the spinal cord 11–1. However, a small but significant number of axons remain ipsilateral. These uncrossed axons may contribute to the return of pain after unilateral neurosurgical lesions of the anterolateral spinal cord have been made to alleviate intractable pain. Most of the nociceptive neurons that ascend into the anterolateral quadrant terminate in the reticular formation of the brainstem (spinoreticular tract) and in the thalamus (spinothalamic tract). The spinoreticular tract, which originates largely in laminae VII and VIII of the dorsal horn of the spinal cord, lacks precise topographical information in that the reticular neurons receive dorsal horn inputs that represent wide receptive fields. The reticular neurons send projections to many brain regions, among which is a prominent input to the thalamus (the reticulothalamic tract). Consistent with this wiring pattern is the theory that the spinoreticular tract contributes to general aspects of pain perception; for example, it may alert an individual to the onset of pain.

Neurons in the spinothalamic tract originate in laminae I and V to VII. A related projection extends from laminae I and V of the dorsal horn to the midbrain (spinomesencephalic tract). A major target of this spinomesencephalic tract is the periaqueductal gray matter (PAG) of the midbrain. Neurons of the PAG represent an important site of convergence between ascending axons that carry sensory information from the spinal cord and descending axons that arise from neurons in brain structures involved in the processing of emotion, such as the amygdala (Chapter 15). Although the PAG receives nociceptive input from the spinal cord, it is not a pain relay nucleus because destruction of the PAG does not alter pain threshold. Rather, the PAG appears to be involved in the brain’s endogenous system of analgesia. Other nociceptive neurons project to the hypothalamus and amygdala, where they most likely mediate some of the autonomic, emotional, and neuroendocrine responses to pain.

Neurons that project from the dorsal horn (or from the trigeminal nucleus) to the thalamus segregate into two divisions. In the lateral division of the spinothalamic tract, axons that relay information from the trunk and extremities terminate in the ventroposterolateral (VPL) nucleus of the thalamus, and axons that relay information from the trigeminal system terminate in the ventroposteromedial (VPM) nucleus of the thalamus. In the medial division, axons terminate mostly in the intralaminar nuclei of the thalamus.

Because the lateral division is phylogenetically recent, it is often called the neospinothalamic tract (see 11–1). It is somatotopically organized and is responsible for the localizing and discriminative aspects of pain. Consistent with this function, the dorsal horn neurons of laminae I and V, from which the neospinothalamic tract originates, have small receptive fields that permit accurate localization of nociceptive stimuli. The VPL and VPM nuclei of the thalamus receive inputs from all modalities of somatic sensation. Less than 10% of the neurons in these thalamic nuclei respond to nociceptive stimuli; the majority respond to touch and proprioceptive inputs from dorsal column neurons that reach the thalamus by way of the medial lemniscus. VPL and VPM neurons, including those that receive nociceptive inputs, project somatotopically to the primary somatic sensory cortex of the parietal lobe.

Because the medial division of the spinothalamic tract is phylogenetically old, it is often called the paleospinothalamic tract. Unlike VPL and VPM neurons, whose projections are restricted to somatosensory cortex, intralaminar thalamic neurons have widespread cortical projections, in particular, to association cortex and prefrontal cortex. The paleospinothalamic tract, like the spinoreticular tract, lacks precise somatotopic organization. The dorsal horn neurons from which it originates, which are typically found in laminae that lie deeper in the spinal cord than those that give rise to the neospinothalamic tract, have large and complex receptive fields; indeed, the receptive fields of some of these cells comprise the entire body. Such large receptive fields are consistent not with the precise localization of pain but with more generalized responses. Thus, it is believed that the paleospinothalamic tract, like spinoreticular, reticulothalamic, and spinohypothalamic projections, is involved in the alerting, emotional, and motivational aspects of pain.

Itch Pathways

While just an annoyance for many people, itch can be a persistent and debilitating symptom for individuals with atopic dermatitis, liver disease, renal disease, or HIV infection. One of the most potent stimulators of itch is histamine acting on H₁ receptors. A class of histamine-responsive unmyelinated C fibers and second-order lamina I dorsal horn neurons 11–6 have been found; these respond poorly, if at all, to nociceptive stimuli. Experiments in mice have found gastrin-releasing peptide (GRP)–containing neurons that project to laminae I and II of the dorsal horn, but the GRP receptor is expressed only in lamina I. Mice lacking the GRP receptor have normal pain responses to thermal, mechanical, and inflammatory stimuli, but have a marked reduction in the itch response to chemicals that cause histamine release from mast cells. Because multiple animal models have been used, it is not clear how the story adds up, but it would be useful to have additional antipruritic compounds because the current histamine H₁ receptor antagonists (which do not cross the blood–brain barrier and thus do not produce drowsiness) have only limited efficacy. Examples of such agents are given in Chapter 6.

Endogenous Opioids and Related Peptides

The endogenous opioid peptides (Chapter 7) are derived from three distinct genes that encode large precursor proteins—proopiomelanocortin (POMC), proenkephalin, and prodynorphin. A fourth precursor, proorphanin FQ–nociceptin, encodes the ligand for the orphanin FQ–nociceptin receptor 11–8. Despite significant homologies with opioid peptides, orphanin FQ–nociceptin may exert antiopioid effects and may promote nociception. Two additional putative opioid peptides, endomorphin 1 and 2, also have been described. In vitro, these peptides bind to the μ opioid receptor with greater affinity and selectivity than that of any other endogenous peptide. However, their status as endogenous signaling peptides will remain uncertain until their mode of synthesis is clarified.

Molecular cloning studies have identified three types of opioid receptors: μ, δ, and κ. Increasing evidence suggests that subtypes of opioid receptors exist, as a result of alternative splicing or posttranslational modifications of μ, δ, and κ receptors, and as a result of their ability to form heterodimers, which exhibit unique ligand binding and functional properties. The relative affinities of different opioid peptides for these receptors are described in Chapter 7. Despite its homology to the δ opioid receptor, ORL₁, the orphanin FQ–nociceptin receptor lacks significant affinity for opioid ligands, including the nonselective opioid antagonist naloxone.

All of the opioid receptors, as well as ORL₁, are seven-transmembrane domain receptors linked to heterotrimeric G_i/o proteins. G_i/o-coupled receptors inhibit the electrical firing of many types of neurons through activation of inwardly rectifying K⁺ channels (GIRKs) and the closing of voltage-gated Ca²⁺ channels (Chapter 2). Opioid receptors also inhibit adenylyl cyclase and the cAMP–protein kinase A pathway (Chapter 4), which may partly mediate their longer-term effects such as tolerance, dependence, withdrawal, and addiction (Chapter 16).

Descending Analgesic Pathways

Because severe pain can disorganize behavior and thereby interfere with the ability to fight or escape danger, mechanisms that suppress pain at times of extreme emergency have significant survival value. Some of the most striking examples of such phenomena have been observed during combat situations in which severely wounded soldiers may deny that they are feeling pain. The threshold level of stress for activating descending analgesic systems must be high, or pain would lose its survival value.

Rodent models of stress-induced analgesia, which can be produced, for example, by foot shock, reveal that this phenomenon is partly opioid-dependent (blocked by naloxone) and partly opioid-independent. A key neural substrate for stress-induced analgesia is the PAG of the brainstem, which receives projections from pain pathways (as discussed earlier) and from the amygdala (Chapter 15). Microinjection of morphine directly into the PAG produces analgesia independently of stress. Microinjections of naloxone into this region partially block stress-induced analgesia. The nonopioid component appears to be dependent on endogenous cannabinoids. Foot shock in rats causes release of two endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide, and the resulting analgesia is blocked by CB₁ receptor antagonists or inverse agonists (eg, rimonabant) (Chapter 8).

The rostral ventral medulla (RVM), a region of the brainstem that includes the nucleus raphe magnus, the nucleus gigantocellularis, and the adjacent reticular formation, is another important site for analgesia. Microinjections of morphine in the RVM produce analgesia; local electrical stimulation of either the PAG or RVM also produces analgesia, presumably causing release of opioids and other analgesic endogenous neurotransmitters.

The PAG projects to the RVM, which in turn projects to the dorsal horn by means of the dorsolateral funiculus of the spinal cord 11–1. Cutting fibers that descend in the dorsolateral funiculus block analgesia produced by electrical stimulation of the PAG. High levels of endogenous opioid peptides and opioid receptors are found within the PAG, RVM, and dorsal horn, and neurons of both the PAG and RVM can be activated by opioids. Because opioid receptors generally produce inhibitory effects on neuronal firing, the ability of endogenous opioid peptides or opiate drugs to activate neurons within the PAG, RVM, and other brain regions is dependent on an anatomic arrangement whereby opioid receptors inhibit inhibitory GABAergic interneurons in these brain regions. Neurons of the RVM that project to the dorsal horn activate enkephalinergic interneurons that are located in the dorsal horn. The neurotransmitter involved in opioid-mediated descending analgesia was long believed to be serotonin from the nucleus raphe magnus (Chapter 6). Indeed, serotonergic neurons do project to the dorsal horn but do not appear to be directly involved in opioid analgesia. Rather, they are thought to play a more complex modulatory role. This theory is consistent with the clinical observation that selective serotonin reuptake inhibitor (SSRI) antidepressants, such as fluoxetine (Chapter 15), lack analgesic properties. This is in contrast to the clinical efficacy of combined serotonin–norepinephrine reuptake inhibitor (SNRI) antidepressants discussed below.

Within the RVM, three physiologic classes of cells project to the dorsal horn. “On” cells are excited by noxious stimuli and inhibited by opioids; “off” cells are inhibited by noxious stimuli and excited by opioids, and neutral cells do not respond to noxious stimuli or opioids. The “off” cells are involved in the classic descending analgesic circuit, and glutamate may be the critical neurotransmitter that conveys descending analgesic information to the dorsal horn. Serotonin is found in neutral cells. Orphanin FQ–nociceptin appears to inhibit opioid-activated descending analgesic outflow from the RVM, and may be responsible for similar activity in the PAG.

Within the dorsal horn, enkephalin-containing interneurons inhibit dorsal horn neurons at the origin of the spinothalamic tract by making direct postsynaptic contact with them. Indirect evidence suggests that presynaptic inhibition of primary nociceptive neurons by opioid-containing interneurons also occurs, but anatomic evidence for this arrangement is lacking.

Opiates

In contrast to local anesthetics, which produce numbness, analgesia produced by stimulation of the PAG or RVM and analgesia produced by morphine are modality-specific with regard to somatic sensation: they suppress only nociception, and do not affect touch, proprioception, or sensation of nonnoxious temperatures. This specificity can be confirmed electrophysiologically: nociceptive neurons in lamina V of the dorsal horn are inhibited by analgesia produced by PAG stimulation or by opiates, but nonnociceptive neurons in lamina III are unaffected by either type of analgesia.

The combination of efficacy in treating pain and, while oft forgotten, the lack of degradation of other sensory modalities has made opiates 11–9 the most important class of drugs for treating severe pain in the history of medicine. The dark side of opiates is well known. They have a significant risk for producing addiction (Chapter 16).

Opiates often are called narcotics because of their potent sedative effects. However, the term narcotic also has a legal definition in the United States and many other countries, which is used for regulatory purposes by the Food and Drug Administration and the Drug Enforcement Agency. For legal purposes, the term narcotic is applied to both opiate and nonopiate drugs with substantial abuse liability. The production, distribution, and prescription of these drugs are closely monitored and regulated. Some of these drugs, such as heroin, have no legally acceptable use outside of research in the United States.

Morphine-like opiates comprise the most important class of compounds used in the treatment of severe acute pain and severe cancer pain. These drugs bind preferentially to the μ opioid receptor, which appears to be the most significant opioid receptor involved in both supraspinal and spinal sites of analgesia. μ receptors are located in areas known to be involved in descending analgesia, including the PAG, RVM, and dorsal horn of the spinal cord. They also are found in regions such as the ventral tegmental area (VTA) of the midbrain and the nucleus accumbens (ventral striatum), where they are responsible for the reinforcing effects of opiates, and in the locus ceruleus (LC) and several other regions that mediate aspects of physical dependence on opiates (Chapter 16). It is now appreciated that several cells of the immune system express μ, δ, and κ opioid receptors, although the relevance of such expression to the analgesic properties of opiate drugs remains an area of active investigation.

The usefulness of morphine-like drugs is limited by their side effects, such as constipation and respiratory depression, and the risks associated with their use, including dependence and addiction. Repeated use of these drugs also results in tolerance to their analgesic effects. Considerable progress has been made in understanding the molecular adaptations that contribute to tolerance at the cellular level, as will be discussed in Chapter 16.

A large number of morphine-like opiates are available clinically 11–3. These drugs differ in their pharmacokinetic properties, particularly with regard to their suitability for oral administration, time of onset, and half-life, and their relative affinity for the μ receptor. Codeine and oxycodone are examples of lower-potency μ agonists; both are effective when administered orally and are commonly combined with aspirin or acetaminophen (eg, Percocet). Dilaudid and fentanyl are examples of very-high-potency μ agonists; the former is suitable for oral administration, whereas the latter is suitable for parenteral or transdermal administration. More recently, opiate agonists with other pharmacological actions have been introduced into clinical practice. Tapentadol, in addition to acting as an agonist of μ receptors, inhibits norepinephrine reuptake that may contribute to its clinical efficacy (see below) and is an agonist at α₂-adrenergic receptors that might ease some side effects (see Chapter 16 for discussion of the latter mechanism). Likewise, tramadol and its active metabolites are agonists of μ receptors and inhibit serotonin and norepinephrine reuptake. As previously discussed, the use of each of these μ agonists is associated with tolerance and physical dependence and the risk for addiction. Indeed, abuse of these various prescription opiates, of low and high potency, is a growing problem in the United States today.

The use of partial agonists at the μ receptor, such as buprenorphine, may be associated with fewer liabilities; it is believed that such agents sufficiently activate the receptor to induce some analgesia but not so much as to induce the molecular adaptations that underlie tolerance and dependence. Partial agonists also may carry a lower risk for abuse because higher doses of the drug do not lead to greater behavioral effects.

Benzomorphan opiate drugs, such as pentazocine, exhibit a high affinity for κ opioid receptors 11–3. Like many opiates, κ receptor agonists produce sedation and miosis. Although in contrast to μ agonists they are often aversive, resulting in negative emotional effects, they can be abused and can produce addictive behaviors. κ receptors are found in the dorsal horn of the spinal cord, in deep cortical layers, and in many other brain regions. Many κ agonist drugs possess properties of μ receptor antagonists and may precipitate withdrawal symptoms in individuals who are dependent on morphine-like drugs. Despite their aversive properties, κ agonists frequently are used instead of μ agonists for obstetric analgesia to reduce the risk of respiratory depression in the newborn.

Considerable effort has been aimed at the development of small-molecule δ agonists during the past two decades; however, only peptides, which lack substantial clinical utility, remain the available ligands with a high affinity for the δ receptor. δ receptors are concentrated not only in the limbic system and in the dorsal horn of the spinal cord but also in regions of the brain that have no clear association with pain. Like κ opioid receptors, δ receptors appear to mediate analgesia at the level of the dorsal horn. These receptors also mediate hypotension and miosis. Efforts are also underway to develop selective agonists at opioid receptor dimers (eg, μ–δ dimers) that could conceivably exhibit unique clinical properties.

Opiate antagonists have clinical utility as well. Naloxone, a nonselective antagonist with a relative affinity of μ > δ > κ, is used to treat heroin and other opiate overdoses. Such treatment often is lifesaving, because opiate overdose can be fatal when it results in severe respiratory depression. A longer-acting nonselective antagonist, naltrexone, is used to prevent relapse to opiate use after detoxification and to limit relapse in alcoholism (Chapter 16).

Aspirin and Nonsteroidal Anti-Inflammatory drugs (NSAIDs)

Aspirin (acetylsalicylic acid), acetaminophen (paracetamol), and the NSAIDs 11–10, including indomethacin, ibuprofen, and naproxen, among others, produce analgesia primarily by diminishing sensitization. They accomplish this by inhibiting the enzyme cyclooxygenase-2 (COX2), which is induced at sites of inflammation and which catalyzes a necessary step in the generation of the sensitizing mediator, prostaglandin E₂ (PGE₂), from arachidonic acid 11–11. Given the multiple signaling pathways that produce sensitization, which do not all involve arachidonic acid metabolism, the analgesic efficacy of aspirin, acetaminophen, and NSAIDs is ultimately limited; nonetheless, they remain the most widely used nonopiate analgesics. All three drugs are also antipyretic (Chapter 10), but only aspirin and the NSAIDs are anti-inflammatory. Acetaminophen’s lack of significant anti-inflammatory effects presumably reflects at least a partially different interaction with cyclooxygenase than aspirin and NSAIDs.

There are two forms of cyclooxygenase, encoded by different genes. Cyclooxygenase-1 (COX1) is constitutively expressed in most cells and is the only isoform in mature platelets. As mentioned above, COX2 is induced by inflammation. In the stomach, COX1-derived prostaglandins protect the gastric mucosa from the acid environment; accordingly, aspirin and nonselective NSAIDs such as ibuprofen, which inhibit COX1, can produce gastric ulceration. This side effect of NSAIDs motivated the development of selective COX2 inhibitors (coxibs), such as rofecoxib and the less selective celecoxib. Unfortunately, selective COX2 inhibitors alter the balance between the eicosanoids, thromboxanes, and prostacyclin leading to cardiovascular risks. Thromboxane A₂ (TXA₂) is produced in platelets from prostaglandin H₂. TXA₂ induces platelet aggregation and is a potent vasoconstrictor. Given its platelet source, it is largely COX1-derived. Prostacyclin is synthesized in endothelial cells from prostaglandin H₂. It has a homeostatic role in limiting platelet aggregation; it also acts as a vasodilator. An unintended consequence of selective COX2 inhibitors is to tip the balance between TXA₂ and prostacyclin toward TXA₂ and thus a prothrombotic state. As is now well known, selective COX2 inhibitors initially became very popular as analgesic and anti-inflammatory drugs, but an increased incidence of cardiovascular side effects has limited their use.

Nonopioid, Non-NSAID Analgesics

The limitations of opiates and NSAIDs have spurred intense interest in the development of analgesics with novel mechanisms of action. Many of the chemical mediators outlined earlier in this chapter represent potential targets for new drugs, although some, including bradykinin and substance P antagonists, have proven disappointing to date. Currently there is interest in CGRP receptor antagonists, especially for the treatment of migraine (Chapter 20).

Descending noradrenergic projections from the LC or from related noradrenergic nuclei in the pons inhibit dorsal horn neurons, and thereby contribute to descending analgesia. The involvement of norepinephrine in descending analgesia may explain the analgesic effects of tricyclic antidepressants, including those selective for norepinephrine reuptake such as desipramine (Chapters 6 and 15), or SNRIs such as duloxetine, which often are effective in the treatment of neuropathic pain. Although many individuals with chronic neuropathic pain experience depression, the analgesic effects of these agents are clearly independent of their antidepressant effects, because the analgesic effects generally occur at lower doses and after shorter periods of treatment. In contrast to tricyclic antidepressants, SSRIs appear to lack analgesic properties. Norepinephrine is believed to exert its antinociceptive effects in part by means of α₂-adrenergic receptors on dorsal horn neurons.

Two structurally related agents used commonly to treat neuropathic pain are pregabalin and gabapentin. Both were developed as anticonvulsants (Chapter 19) and were thought originally to act by promoting GABA function in the central nervous system (CNS). More recently, however, both drugs have been shown to bind with high affinity to the α₂δ subunit of voltage-gated Ca²⁺ channels and to thereby promote the trafficking of those channels away from the plasma membrane. There is now convincing evidence that this mechanism is responsible for the antiseizure and analgesic properties of the drugs. This view is consistent with evidence that blockers of L-type (eg, verapamil, diltiazem) or N-type (ziconotide) Ca²⁺ channels (Chapter 2) offer some benefit in combination with opiates in the treatment of chronic pain syndromes. Precisely how a reduction in Ca²⁺ channel activity mediates analgesia remains unknown, although a reduction in glutamate release has been suggested. The α₂δ subunit appears to control the trafficking of other plasma membrane proteins, in addition to Ca²⁺ channels, which might also contribute to the clinical actions of these drugs.

The unmet need for more effective treatments for chronic pain syndromes has driven the evaluation of diverse types of other agents. Ketamine, a noncompetitive antagonist of the NMDA glutamate receptor, is approved by the US Food and Drug Administration for intravenous or intramuscular use as an anesthetic agent (Chapter 13). There are numerous reports of analgesic efficacy at subanesthetic doses; indeed, there is interest in the development of other formulations of ketamine (eg, for intranasal administration) for the treatment of chronic pain. There is also interest in ketamine for the treatment of depression (Chapter 15); meanwhile, ketamine is considered a drug of abuse and hence its use carries some addiction liability (Chapter 16).

Other ion channel blockers are under consideration for the treatment of chronic pain. Given their role in the transmission of pain signals as discussed in earlier sections of this chapter, there are efforts to develop antagonists of several types of TRP channels as novel analgesic agents. TRPV₁ or TRPV₄ antagonists, in particular, are under development. Likewise, given the role of voltage-gated Na⁺ channels in nerve conduction, it is not surprising that several Na⁺ channel blockers, for example, lidocaine, mexiletine, phenytoin, carbamazepine, and lamotrigine (Chapter 19), show some utility in the treatment of chronic pain. However, these agents are not selective for Na⁺ channels expressed in peripheral nerves and accordingly their use is associated with many side effects, providing a rationale to develop drugs that block Na⁺ channels enriched in peripheral nociceptors. The fact that Na_V1.7, Na_V1.8, and Na_V1.9 channel subunits are enriched in DRG and trigeminal ganglion neurons has driven the generation of antagonists selective for these subunits. The observation that rare loss-of-function mutations in Na_V1.7 in humans are associated with a complete loss of pain sensation, and the very dangerous risks this brings, provides human validation for this therapeutic approach. Modification of several toxins (eg, tetrodotoxin from the puffer fish or crotamine compounds from rattlesnakes) that are known to block voltage-gated Na⁺ channels is another strategy by which to find pain-easing channel blockers.

Finally, there is interest in NGF and its TrkA receptor, molecules which, as noted earlier, contribute to normal nociception. Moreover, families with loss-of-function mutations in TrkA show loss of pain sensation. Current strategies are focusing on developing small-molecule antagonists of TrkA or neutralizing antibodies directed against NGF (eg, tanezumab). Meanwhile, many patients continue to benefit greatly from a range of nonmedication treatments, including acupuncture, hypnosis, and meditation.