Pain Management

Definition of Pain by the International Association for the Study of Pain

"an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage." This definition recognizes the interplay between the objective, physiological sensory aspects of pain and its subjective, emotional, and psychological components. e response to pain can be highly variable among different individuals as well as in the same person at different times.

What is the Triple Response of Lewis?

- a red flush around the site of injury (flare) - local tissue edema - sensitization to noxious stimuli

Multimodal Analgesia

1098-1103

What area of the body contains no nociceptors?

A few organs, such as the brain, lack nociceptors altogether; however, the brain's meningeal coverings do contain nociceptors.

Epicritic Sensation

AKA non-noxious. Epicritic sensations (light touch, pressure, proprioception, and temperature discrimination) are characterized by low-threshold receptors and are generally conducted by large myelinated nerve fibers.

Protopathic Sensation

AKA noxious. Protopathic sensations (pain) are detected by high-threshold receptors and conducted by smaller, lightly myelinated (Aδ) and unmyelinated (C) nerve fibers.

Paresthesia

Abnormal sensation perceived without an apparent stimulus

Anesthesia

Absence of all sensation

Analgesia

Absence of pain perception

Segmental Inhibition

Activation of large afferent fibers subserving sensation inhibits WDR neuron and spinothalamic tract activity. Moreover, activation of noxious stimuli in noncontiguous parts of the body inhibits WDR neurons at other levels, which may explain why pain in one part of the body inhibits pain in other parts. Th ese two phenomena support a "gate" theory for pain processing in the spinal cord. Glycine and γ-aminobutyric acid (GABA) are amino acids that function as inhibitory neurotransmitters and likely play an important role in segmental inhibition of pain in the spinal cord. Antagonism of glycine and GABA results in powerful facilitation of WDR neurons and produces allodynia and hyperesthesia. Th ere are two subtypes of GABA receptors: GABA A , of which muscimol is an agonist, and GABA B , of which baclofen is an agonist. Segmental inhibition appears to be mediated by GABA B receptor activity. The GABA A receptor functions as a Cl − channel, and benzodiazepines activate this channel. Activation of glycine receptors also increases Cl − conductance across neuronal cell membranes. Th e action of glycine is more complex than that of GABA, because the former also has a facilitatory (excitatory) eff ect on the NMDA receptor. Adenosine also modulates nociceptive activity in the dorsal horn. At least two receptors are known: A 1 , which inhibits adenyl cyclase, and A 2 , which stimulates adenyl cyclase. Th e A 1 receptor mediates adenosine's antinociceptive action. Methylxanthines can reverse this eff ect through phosphodiesterase inhibition.

Acute Pain

Acute pain is caused by noxious stimulation due to injury, a disease process, or the abnormal function of muscle or viscera. It is usually nociceptive. Nociceptive pain serves to detect, localize, and limit tissue damage. Four physiological processes are involved: transduction, transmission, modulation, and perception. This type of pain is typically associated with a neuroendocrine stress response that is proportional to the pain's intensity. Its most common forms include post-traumatic, postoperative, and obstetric pain as well as pain associated with acute medical illnesses, such as myo- cardial infarction, pancreatitis, and renal calculi. Most forms of acute pain are self-limited or resolve with treatment in a few days or weeks. When pain fails to resolve because of either abnormal healing or inadequate treatment, it becomes chronic. Two types of acute (nociceptive) pain—somatic and visceral—are differentiated based on origin and features.

Systemic Responses to Acute Pain

Acute pain is typically associated with a neuroendocrine stress response that is proportional to pain intensity. Th e pain pathways mediating the aff erent limb of this response are discussed above. Th e eff erent limb is mediated by the sympathetic nervous and endocrine systems. Sympathetic activation increases eff erent sympathetic tone to all viscera and releases catecholamines from the adrenal medulla. Th e hormonal response results from increased sympathetic tone and from hypothalamically mediated refl exes. Moderate to severe acute pain, regardless of site, can aff ect the function of nearly every organ and may adversely aff ect perioperative morbidity and mortality.

Respiratory Effects of Pain

An increase in total body oxygen consumption and carbon dioxide production necessitates a concomitant increase in minute ventilation. Th e latter increases the work of breathing, particularly in patients with underlying lung disease. Pain due to abdominal or thoracic incisions further compromises pulmonary function because of guarding (splinting). Decreased movement of the chest wall reduces tidal volume and functional residual capacity; this promotes atelectasis, intrapulmonary shunting, hypoxemia, and, less commonly, hypoventilation. Reductions in vital capacity impair coughing and clearing of secretions. Regardless of the pain's location, prolonged bed rest or immobilization can produce similar changes in pulmonary function.

Psychological Effects of Pain

Anxiety and sleep disturbances are common reactions to acute pain. With prolonged duration of the pain, depression is not unusual. Some patients react with frustration and anger that may be directed at family, friends, or the medical staff .

Second Order Neurons

As afferent fibers enter the spinal cord, they segregate according to size, with large, myelinated fi bers becoming medial, and small, unmyelinated fi bers becoming lateral. Pain fibers may ascend or descend one to three spinal cord segments in Lissauer's tract before synapsing with second-order neurons in the gray matter of the ipsilateral dorsal horn. In many instances they communicate with second-order neurons through interneurons.

Alternate Pain Pathways for 2nd Order Neurons

As with epicritic sensation, pain fi bers ascend diffusely, ipsilaterally, and contralaterally; some patients continue to perceive pain following ablation of the contralateral spinothalamic tract, and therefore other ascending pain pathways are also important. Th e spinoreticular tract is thought to mediate arousal and autonomic responses to pain. Th e spinomesencephalic tract may be important in activating antinociceptive, descending pathways, because it has some projections to the periaqueductal gray. The spinohypothalamic and spinotelencephalic tracts activate the hypothalamus and evoke emotional behavior. The spinocervical tract ascends uncrossed to the lateral cervical nucleus, which relays the fibers to the contralateral thalamus; this tract is likely a major alternative pathway for pain. Lastly, some fibers in the dorsal columns (which mainly carry light touch and proprioception) are responsive to pain; they ascend medially and ipsilaterally.

Central Facilitation of Pain

At least three mechanisms are responsible for central sensitization in the spinal cord: 1. Wind-up and sensitization of second-order neurons. WDR neurons increase their frequency of discharge with the same repetitive stimuli and exhibit prolonged discharge, even aft er aff erent C fi ber input has stopped. 2. Receptor fi eld expansion. Dorsal horn neurons increase their receptive fi elds such that adjacent neurons become responsive to stimuli (whether noxious or not) to which they were previously unresponsive. 3. Hyperexcitability of fl exion refl exes. Enhancement of fl exion refl exes is observed both ipsilaterally and contralaterally. Neurochemical mediators of central sensitization include substance P, CGRP, vasoactive intestinal peptide (VIP), cholecystokinin (CCK), angiotensin, and galanin, as well as the excitatory amino acids l-glutamate and l-aspartate. Th ese substances trigger changes in membrane excitability by interacting with G protein-coupled membrane receptors on neurons ( Figure 47-5 ). Glutamate and aspartate play important roles in wind-up, via activation of N -methyl- d-aspartate (NMDA) and other receptor mechanisms, and in the induction and maintenance of central sensitization. Activation of NMDA receptors also induces nitric oxide synthetase, increasing formation of nitric oxide. Both prostaglandins and nitric oxide facilitate the release of excitatory amino acids in the spinal cord. Th us, COX inhibitors such as ASA and NSAIDs have important analgesic actions in the spinal cord.

What types of nociceptor receptors have been identified?

At least two nociceptor receptors (containing ion channels in nerve endings) have been identifi ed, TRPV1 and TRPV2. Both respond to high temperatures. Capsaicin stimulates the TRPV1 receptor.

Cardiovascular Effects of Pain

Cardiovascular eff ects are oft en prominent and include hypertension, tachycardia, enhanced myocardial irritability, and increased systemic vascular resistance. Cardiac output increases in most normal patients but may decrease in patients with compromised ventricular function. Because of the increase in myocardial oxygen demand, pain can worsen or precipitate myocardial ischemia.

Patterns of Referred Pain

Central diaphragm C4 Lungs T2-T6 Aorta T1-L2 Heart T1-T4 Esophagus T3-T8 Pancreas and spleen T5-T10 Stomach, liver, and gallbladder T6-T9 Adrenals T8-L1 Small intestine T9-T11 Colon T10-L1 Kidney, ovaries, and testes T10-L1 Ureters T10-T12 Uterus T11-L2 Bladder and prostate S2-S4 Urethra and rectum S2-S4

Chronic Pain

Chronic pain is pain that persists beyond the usual course of an acute disease or aft er a reasonable time for healing to occur; this healing period typically can vary from 1 to 6 months. Chronic pain may be nociceptive, neuropathic, or mixed. A distinguishing feature is that psychological mechanisms or environmental factors frequently play a major role. Patients with chronic pain oft en have attenuated or absent neuroendocrine stress responses and have prominent sleep and aff ective (mood) disturbances. Neuropathic pain is classically paroxysmal and lancinating, has a burning quality, and is associated with hyperpathia. When it is also associated with loss of sensory input (eg, amputation) into the central nervous system, it is termed *deafferentation pain*. When the sympathetic system plays a major role, it is often termed *sympathetically maintained pain*.

Pathophysiology of Chronic Pain

Chronic pain may be caused by a combination of peripheral, central, and psychological mechanisms. Sensitization of nociceptors plays a major role in the origin of pain associated with peripheral mechanisms, such as chronic musculoskeletal and visceral disorders. Neuropathic pain involves peripheral-central and central neural mechanisms that are complex and generally associated with partial or complete lesions of peripheral nerves, dorsal root ganglia, nerve roots, or more central structures ( Table 47-5 ). Peripheral mechanisms include spontaneous discharges; sensitization of receptors to mechanical, thermal, and chemical stimuli; and up-regulation of adrenergic receptors. Neural infl ammation may also be present. Systemic administration of local anesthetics and anticonvulsants has been shown to suppress the spontaneous fi ring of sensitized or traumatized neurons. Th is observation is supported by the effi cacy of agents such as lidocaine, mexiletine, and carbamazepine in many patients with neuropathic pain. Central mechanisms include loss of segmental inhibition, wind-up of WDR neurons, spontaneous discharges in deaff erentated neurons, and reorganization of neural connections. Th e sympathetic nervous system appears to play a major role in some patients with chronic pain. Th e effi cacy of sympathetic nerve blocks in some of these patients supports the concept of sympathetically maintained pain . Painful disorders that oft en respond to sympathetic blocks include complex regional pain syndrome, deaff erentation syndromes due to nerve avulsion or amputations, and postherpetic neuralgia. However, the simplistic theory of heightened sympathetic activity resulting in vasoconstriction, edema, and hyperalgesia fails to account for the warm and erythematous phase observed in some patients. Similarly, clinical and experimental observations do not satisfactorily support the theory of ephaptic transmission between pain fi bers and demyelinated sympathetic fi bers. Psychological mechanisms or environmental factors are rarely the sole mechanisms for chronic pain but are commonly seen in combination with other mechanisms ( Table 47-6 ).

Deep Somatic Nociceptors

Deep somatic nociceptors are less sensitive to noxious stimuli than cutaneous nociceptors but are easily sensitized by infl ammation. Th e pain arising from them is characteristically dull and poorly localized. Specifi c nociceptors exist in muscles and joint capsules, and they respond to mechanical, thermal, and chemical stimuli.

Deep vs. Superficial Somatic Pain

Deep somatic pain arises from muscles, tendons, joints, or bones. In contrast to superficial somatic pain, it usually has a dull, aching quality and is less well localized. An additional feature is that both the intensity and duration of the stimulus affect the degree of localization. For example, pain following brief minor trauma to the elbow joint is localized to the elbow, but severe or sustained trauma often causes pain in the whole arm.

Hypalgesia/Hypoalgesia

Diminished response to noxious stimulation (eg, pinprick)

GI and Urinary Effects of Pain

Enhanced sympathetic tone increases sphincter tone and decreases intestinal and urinary motility, promoting ileus and urinary retention, respectively. Hypersecretion of gastric acid can promote stress ulceration and worsen the consequences of pulmonary aspiration. Nausea, vomiting, and constipation are common.

Radiculopathy

Functional abnormality of one or more nerve roots

Pain Management

In a general sense applies to the entire discipline of anesthesiology, but its modern usage more speci cally involves management of pain throughout the perioperative period as well as nonsurgical pain in both inpa- tient and outpatient settings.

How are Epicritic and Protopathic Pain Transduced?

In contrast to epicritic sensation, which may be transduced by specialized end organs on the afferent neuron (eg, pacinian corpuscle for touch), protopathic sensation is transduced mainly by free nerve endings.

Hyperesthesia

Increased response to mild stimulation

Hyperalgesia

Increased response to noxious stimulation

Spinal Cord Laminae

Lamina: Predominant Function/Input/Name I: Somatic nociception thermoreception/Aδ, C/Marginal layer II: Somatic nociception thermoreception/C, Aδ/Substantia gelatinosa III: Somatic mechanoreception/Aβ, Aδ/Nucleus proprius IV: Mechanoreception/Aβ, Aδ/Nucleus proprius V: Visceral and somatic nociception and mechanoreception/Aβ, Aδ, (C)/Nucleus proprius WDR neurons VI: Mechanoreception/Aβ/Nucleus proprius VII: Sympathetic Intermediolateral column VIII:/Aβ/Motor horn IX: Motor/Aβ/Motor horn X:/Aβ, (Aδ)/Central canal

Modulation of Pain

Modulation of pain occurs peripherally at the nociceptor, in the spinal cord, and in supraspinal structures. Th is modulation can either inhibit (suppress) or facilitate (intensify) pain.

Peripheral Modulation of Pain

Modulation of pain occurs peripherally at the nociceptor, in the spinal cord, and in supraspinal structures. Th is modulation can either inhibit (suppress) or facilitate (intensify) pain.

Secondary Hyperalgesia

Neurogenic infl ammation, also called secondary hyperalgesia, plays an important role in peripheral sensitization following injury. It is manifested by the "triple response (of Lewis)" of a red fl ush around the site of injury (fl are), local tissue edema, and sensitization to noxious stimuli. Secondary hyperalgesia is primarily due to antidromic (opposite the direction a normal nerve impulse travels) release of substance P (and probably CGRP). Substance P degranulates histamine and 5-HT, vasodilates blood vessels, causes tissue edema, and induces the formation of leukotrienes. Th e neural origin of this response is supported by the following fi ndings: (1) it can be produced by electrical stimulation of a sensory nerve, (2) it is not observed in denervated skin, and (3) it is diminished by injection of a local anesthetic. Capsaicin applied topically in a gel, cream, or patch depletes substance P and diminishes neurogenic infl ammation, and is useful for some patients with postherpetic neuralgia.

Neuropathic Pain

Neuropathic pain is the result of injury or acquired abnormalities of periph- eral or central neural structures.

Major Neurotransmitters Mediating or Modulating Pain

Neurotransmitter/Receptor/Effect on Nociception Substance P Neurokinin-1 Excitatory Calcitonin gene-related peptide Excitatory Glutamate NMDA, AMPA, kainate, quisqualate Excitatory Aspartate NMDA, AMPA, kainate, quisqualate Excitatory Adenosine triphosphate (ATP) P 1 , P 2 Excitatory Somatostatin Inhibitory Acetylcholine Muscarinic Inhibitory Enkephalins μ, δ, κ Inhibitory β-Endorphin μ, δ, κ Inhibitory Norepinephrine α 2 Inhibitory Adenosine A 1 Inhibitory Serotonin 5-HT 1 (5-HT 3 ) Inhibitory γ-Aminobutyric acid (GABA) A, B Inhibitory Glycine Inhibitory

Nociceptive Pain

Nociceptive pain is caused by activation or sensitization of peripheral nociceptors, specialized receptors that transduce noxious stimuli.

How are Nociceptors Characterized?

Nociceptors are characterized by a high threshold for activation and encode the intensity of stimulation by increasing their discharge rates in a graded fashion. Following repeated stimulation, they characteristically display delayed adaptation, sensitization,and after discharges.

Cutaneous Nociceptors

Nociceptors are present in both somatic and visceral tissues. Primary afferent neurons reach tissues by traveling along spinal somatic, sympathetic, or parasympathetic nerves. Somatic nociceptors include those in skin (cutaneous) and deep tissues (muscle, tendons, fascia, and bone), whereas visceral nociceptors include those in internal organs.

How Is Pain Originating from the Head Transmitted by First Order Neurons?

Pain fi bers originating from the head are carried by the trigeminal (V), facial (VII), glossopharyngeal (IX), and vagal (X) nerves. Th e gasserian ganglion contains the cell bodies of sensory fi bers in the ophthalmic, maxillary, and mandibular divisions of the trigeminal nerve. Cell bodies of fi rst-order aff erent neurons of the facial nerve are located in the geniculate ganglion ; those of the glossopharyngeal nerve lie in its superior and petrosal ganglia ; and those of the vagal nerve are located in the jugular ganglion (somatic) and the ganglion nodosum (visceral). The proximal axonal processes of the first-order neurons in these ganglia reach the brainstem nuclei via their respective cranial nerves, where they synapse with second-order neurons in brainstem nuclei. V: Gasserian Ganglion VII: Geniculate Ganglion IX: Superior and Petrosal Ganglia X: Jugular Ganglion (somatic) and Ganglion Nodosum (visceral)

Anesthesia Dolorosa

Pain in an area that lacks sensation

Neuralgia

Pain in the distribution of a nerve or a group of nerves

Pain Pathway Overview

Pain is conducted along three neuronal pathways that transmit noxious stimuli from the periphery to the cerebral cortex ( Figure 47-1 ). Th e cell bodies of primary afferent neurons are located in the dorsal root ganglia, which lie in the vertebral foramina at each spinal cord level. Each neuron has a single axon that bifurcates, sending one end to the peripheral tissues it innervates and the other into the dorsal horn of the spinal cord. In the dorsal horn, the primary aff erent neuron synapses with a second-order neuron whose axon crosses the midline and ascends in the contralateral spinothalamic tract to reach the thalamus. Second-order neurons synapse in thalamic nuclei with third-order neurons, which in turn send projections through the internal capsule and corona radiata to the postcentral gyrus of the cerebral cortex ( Figure 47-2 ).

How can Pain be Classified?

Pain may be classified according to patho- physiology (eg, nociceptive or neuropathic pain), etiology (eg, arthritis or cancer pain), or the affected area (eg, headache or low back pain). Such classifications are useful in the selection of treatment modalities and drug therapy.

Parietal Pain

Parietal pain is typically sharp and oft en described as a stabbing sensation that is either localized to the area around the organ or referred to a distant site

Allodynia

Perception of an ordinarily nonnoxious stimulus as pain

Hyperpathia

Presence of hyperesthesia, allodynia, and hyperalgesia usually associated with overreaction, and persistence of the sensation after the stimulus

Hypesthesia/Hypoesthesia

Reduced cutaneous sensation (eg, light touch, pressure, or temperature)

Primary Hyperalgesia

Sensitization of nociceptors results in a decrease in threshold, an increase in the frequency response to the same stimulus intensity, a decrease in response latency, and spontaneous fi ring even aft er cessation of the stimulus ( aft erdischarges ). Such sensitization commonly occurs with injury and following application of heat. Primary hyperalgesia is mediated by the release of noxious substances from damaged tissues. Histamine is released from mast cells, basophils, and platelets, whereas serotonin is released from mast cells and platelets. Bradykinin is released from tissues following activation of factor XII. Bradykinin activates free nerve endings via specifi c B1 and B2 receptors. Prostaglandins are produced following tissue damage by the action of phospholipase A 2 on phospholipids released from cell membranes to form arachidonic acid ( Figure 47-5 ). Th e cyclooxygenase (COX) pathway then converts the latter into endoperoxides , which in turn are transformed into prostacyclin and prostaglandin E 2 (PGE 2 ). PGE 2 directly activates free nerve endings, whereas prostacyclin potentiates the edema from bradykinin. The lipoxygenase pathway converts arachidonic acid into hydroperoxy compounds, which are subsequently converted into leukotrienes . Th e role of the latter is not well defi ned, but they appear to potentiate certain types of pain. Pharmacological agents such as acetylsalicylic acid (ASA, or aspirin), acetaminophen, and nonsteroidal antiinfl ammatory drugs (NSAIDs) produce analgesia by inhibition of COX. Th e analgesic eff ect of corticosteroids is likely the result of inhibition of prostaglandin production through blockade of phospholipase A 2 activation.

Chemical Mediators of Pain

Several neuropeptides and excitatory amino acids function as neurotransmitters for aff erent neurons subserving pain ( Table 47-4 ). Many, if not most, of these neurons contain more than one neurotransmitter, which are simultaneously released. The most important of these peptides are substance P and calcitonin gene-related peptide (CGRP). Glutamate is the most important excitatory amino acid. Both opioid and α 2 -adrenergic receptors have been described on or near the terminals of unmyelinated peripheral nerves. Although their physiological role is not clear, the latter may explain the observed analgesia of peripherally applied opioids, particularly in the presence of infl ammation.

Supraspinal Inhibition

Several supraspinal structures send fi bers down the spinal cord to inhibit pain in the dorsal horn. Important sites of origin for these descending pathways include the periaqueductal gray, reticular formation, and nucleus raphe magnus (NRM). Stimulation of the periaqueductal gray area in the midbrain produces widespread analgesia in humans. Axons from these tracts act presynaptically on primary aff erent neurons and postsynaptically on second-order neurons (or interneurons). Th ese pathways mediate their antinociceptive action via α 2 -adrenergic, serotonergic, and opiate (μ, δ, and κ) receptor mechanisms. Th e role of monoamines in pain inhibition explains the analgesic effi cacy of antidepressants that block reuptake of catecholamines and serotonin. Inhibitory adrenergic pathways originate primarily from the periaqueductal gray area and the reticular formation. Norepinephrine mediates this action via activation of presynaptic or postsynaptic α 2 receptors. At least part of the descending inhibition from the periaqueductal gray is relayed fi rst to the NRM and medullary reticular formation; serotonergic fi bers from the NRM then relay the inhibition to dorsal horn neurons via the dorsolateral funiculus . Th e endogenous opiate system (primarily the NRM and reticular formation) acts via methionine enkephalin, leucine enkephalin, and β-endorphin, all of which are antagonized by naloxone. Th ese opioids act presynaptically to hyperpolarize primary aff erent neurons and inhibit the release of substance P; they also appear to cause some postsynaptic inhibition. Exogenous opioids preferentially act postsynaptically on the second-order neurons or interneurons in the substantia gelatinosa.

2nd Order Integration of Sympathetic and Motor Systems

Somatic and visceral aff erents are fully integrated with the skeletal motor and sympathetic systems in the spinal cord, brainstem, and higher centers. Aff erent dorsal horn neurons synapse both directly and indirectly with anterior horn motor neurons. Th ese synapses are responsible for the refl ex muscle activity—whether normal or abnormal—that is associated with pain. In a similar fashion, synapses between aff erent nociceptive neurons and sympathetic neurons in the intermediolateral column result in refl ex sympathetically mediated vasoconstriction, smooth muscle spasm, and the release of catecholamines, both locally and from the adrenal medulla.

Somatic Pain

Somatic pain can be further classified as superficial or deep. Superficial somatic pain is due to nociceptive input arising from skin, subcutaneous tissues, and mucous membranes. It is characteristically well localized and described as a sharp, pricking, throbbing, or burning sensation.

Rexed's Laminae

Spinal cord gray matter was divided by Rexed into 10 laminae ( Figure 47-3 and Table 47-3 ). Th e fi rst six laminae, which make up the dorsal horn, receive all aff erent neural activity and represent the principal site of modulation of pain by ascending and descending neural pathways. Second-order neurons are either nociceptive-specifi c or wide dynamic range (WDR) neurons. Nociceptive- specifi c neurons serve only noxious stimuli, but WDR neurons also receive nonnoxious aff erent input from Aβ, Aδ, and C fi bers. Nociceptive-specifi c neurons are arranged somatotopically in lamina I and have discrete, somatic receptive fi elds; they are normally silent and respond only to high-threshold noxious stimulation, poorly encoding stimulus intensity. WDR neurons are the most prevalent cell type in the dorsal horn. Although they are found throughout the dorsal horn, WDR neurons are most abundant in lamina V. During repeated stimulation, WDR neurons characteristically increase their fi ring rate exponentially in a graded fashion ("wind-up"), even with the same stimulus intensity. They also have large receptive fields compared with nociceptive-specific neurons. Most nociceptive C fibers send collaterals to, or terminate on, second-order neurons in laminae I and II, and, to a lesser extent, in lamina V. In contrast, nociceptive Aδ fi bers synapse mainly in laminae I and V, and, to a lesser degree, in lamina X. Lamina I responds primarily to noxious (nociceptive) stimuli from cutaneous and deep somatic tissues. Lamina II, also called the substantia gelatinosa , contains many interneurons and is believed to play a major role in processing and modulating nociceptive input from cutaneous nociceptors. It is also of special interest because it is believed to be a major site of action for opioids. Laminae III and IV primarily receive nonnociceptive sensory input. Laminae VIII and IX make up the anterior (motor) horn. Lamina VII is the intermediolateral column and contains the cell bodies of preganglionic sympathetic neurons. Visceral aff erents terminate primarily in lamina V, and, to a lesser extent, in lamina I. Th ese two laminae represent points of central convergence between somatic and visceral inputs. Lamina V responds to both noxious and nonnoxious sensory input and receives both visceral and somatic pain aff events. The phenomenon of convergence between visceral and somatic sensory input is manifested clinically as referred pain (see Table 47-2 ). Compared with somatic fibers, visceral nociceptive fibers are fewer in number, more widely distributed, proportionately activate a larger number of spinal neurons, and are not organized somatotopically.

Endocrine Effects of Pain

Stress increases catabolic hormones (catecholamines, cortisol, and glucagon) and decreases anabolic hormones (insulin and testosterone). Patients develop a negative nitrogen balance, carbohydrate intolerance, and increased lipolysis. Th e increase in cortisol, renin, angiotensin, aldosterone, and antidiuretic hormone results in sodium retention, water retention, and secondary expansion of the extracellular space.

Hematological Effects Effects of Pain

Stress-mediated increases in platelet adhesiveness, reduced fi brinolysis, and hypercoagulability have been reported.

Substance P

Substance P is an 11 amino acid peptide that is synthesized and released by fi rst-order neurons both peripherally and in the dorsal horn. Also found in other parts of the nervous system and the intestines, it facilitates transmission in pain pathways via neurokinin- 1 receptor activation. In the periphery, substance P neurons send collaterals that are closely associated with blood vessels, sweat glands, hair follicles, and mast cells in the dermis. Substance P sensitizes nociceptors, degranulates histamine from mast cells and 5-HT from platelets, and is a potent vasodilator and chemoattractant for leukocytes. Substance P-releasing neurons also innervate the viscera and send collateral fi bers to paravertebral sympathetic ganglia; intense stimulation of viscera, therefore, can cause direct postganglionic sympathetic discharge.

Spinothalamic Tract

Th e axons of most second-order neurons cross the midline close to their dermatomal level of origin (at the anterior commissure) to the contralateral side of the spinal cord before they form the spinothalamic tract and send their fi bers to the thalamus, the reticular formation , the nucleus raphe magnus , and the periaqueductal gray. The spinothalamic tract, which is classically considered the major pain pathway, lies anterolaterally in the white matter of the spinal cord ( Figure 47-4 ). Th is ascending tract can be divided into a lateral and a medial tract. The lateral spinothalamic (neospinothalamic) tract projects mainly to the ventral posterolateral nucleus of the thalamus and carries discriminative aspects of pain, such as location, intensity, and duration. The medial spinothalamic (paleospinothalamic) tract projects to the medial thalamus and is responsible for mediating the autonomic and unpleasant emotional perceptions of pain. Some spinothalamic fibers also project to the periaqueductal gray and thus may be an important link between the ascending and descending pathways. Collateral fibers also project to the reticular activating system and the hypothalamus; these are likely responsible for the arousal response to pain.

Systemic Responses to Chronic Pain

Th e neuroendocrine stress response is generally observed only in patients with severe recurring pain due to peripheral (nociceptive) mechanisms and in patients with prominent central mechanisms such as pain associated with paraplegia. It is attenuated or absent in most patients with chronic pain. Sleep and aff ective disturbances, particularly depression, are oft en prominent. Many patients also experience signifi cant changes in appetite (increase or decrease) and stresses on social relationships.

Immune Effects of Pain

Th e neuroendocrine stress response produces leukocytosis and has been reported to depress the reticuloendothelial system. Th e latter predisposes patients to infection. Stress-related immunodepression may also enhance tumor growth and metastasis.

Which areas of the body are almost exclusively innervated by nociceptive A delta and C fibers?

The cornea and tooth pulp

First Order Neurons

The majority of first-order neurons send the proximal end of their axons into the spinal cord via the dorsal (sensory) spinal root at each cervical, thoracic, lumbar, and sacral level. Some unmyelinated afferent (C) fi bers have been shown to enter the spinal cord via the ventral nerve (motor) root, accounting for observations that some patients continue to feel pain even after transection of the dorsal nerve root (rhizotomy) and report pain following ventral root stimulation. Once in the dorsal horn, in addition to synapsing with second-order neurons, the axons of first-order neurons may synapse with interneurons, sympathetic neurons, and ventral horn motor neurons.

Forms of Chronic Pain

The most common forms of chronic pain include those associated with musculoskeletal disorders, chronic visceral disorders, lesions of peripheral nerves, nerve roots, or dorsal root ganglia (including diabetic neuropathy, causalgia, phantom limb pain, and postherpetic neuralgia), lesions of the central nervous system (stroke, spinal cord injury, and multiple sclerosis), and cancer pain. The pain of most musculoskeletal disorders (eg, rheumatoid arthritis and osteoarthritis) is primarily nociceptive, whereas pain associated with peripheral or central neural disorders is primarily neuropathic. The pain associated with some disorders, eg, cancer and chronic back pain (particularly after surgery), is often mixed. Some clinicians use the term chronic benign pain when pain does not result from cancer. This terminology should be discouraged, however, because pain is never benign from the patient's point of view, regardless of its cause.

Referred Visceral and Parietal Pain

The phenomenon of visceral or parietal pain referred to cutaneous areas results from patterns of embryological development and migration of tissues, and the convergence of visceral and somatic aff erent input into the central nervous system. Thus, pain associated with disease processes involving the peritoneum or pleura over the central diaphragm is frequently referred to the neck and shoulder, whereas pain from disease processes aff ecting the parietal surfaces of the peripheral diaphragm is referred to the chest or upper abdominal wall.

Nociception

The term nociception is derived from noci (Latin for harm or injury) and is used to describe neural responses to traumatic or noxious stimuli. All nociception produces pain, but not all pain results from nociception. Many patients experience pain in the absence of noxious stimuli. It is there- fore clinically useful to divide pain into one of two categories: (1) acute pain, which is primarily due to nociception, and (2) chronic pain, which may be due to nociception, but in which psychological and behavioral factors o en play a major role.

How does pain perception differ between sexes?

There are differences in pain perception related to gender and age. Research has confirmed differences in pain experiences and coping strategies between genders, and there is ongoing investigation into exactly how this processing differs. Brain activation di ers between genders, with men particularly influenced by the type and intensity of a noxious stimulus. Brain imaging patterns differ as well. Some of these differences decrease with age and may disappear after age 40.

What do polymodal mechanoheat nociceptors respond to?

They respond to excessive pressure, extremes of temperature (>42°C and <40°C), and noxious substances such as bradykinin, histamine, serotonin (5-hydroxytryptamine or 5-HT), H + , K + , some prostaglandins, capsaicin, and possibly adenosine triphosphate. Polymodal nociceptors are slow to adapt to strong pressure and display heat sensitization

Third Order Neurons

Third-order neurons are located in the thalamus and send fi bers to somatosensory areas I and II in the postcentral gyrus of the parietal cortex and the superior wall of the sylvian fissure, respectively. Perception and discrete localization of pain take place in these cortical areas. Although most neurons from the lateral thalamic nuclei project to the primary somatosensory cortex, neurons from the intralaminar and medial nuclei project to the anterior cingulate gyrus and are likely involved in mediating the suffering and emotional components of pain.

Central Inhibition of Pain

Transmission of nociceptive input in the spinal cord can be inhibited by segmental activity in the cord itself, as well as by descending neural activity from supraspinal centers.

True Visceral Pain

True visceral pain is dull, diffuse, and usually midline. It is frequently associated with abnormal sympathetic or parasympathetic activity causing nausea, vomiting, sweating, and changes in blood pressure and heart rate.

What types of nociceptors exist? Which ones are the most prevalent?

Types include (1) mechanonociceptors , which respond to pinch and pinprick, (2) silent nociceptors , which respond only in the presence of infl ammation, and (3) polymodal mechanoheat nociceptors . The last are most prevalent.

Dysesthesia

Unpleasant or abnormal sensation with or without a stimulus

Visceral Pain

Visceral acute pain is due to a disease process or abnormal function involving an internal organ or its covering (eg, parietal pleura, pericardium, or peritoneum). Four subtypes are described: (1) true localized visceral pain (2) localized parietal pain (3) referred visceral pain (4) referred parietal pain.

Visceral Nociceptors

Visceral organs are generally insensitive tissues that mostly contain silent nociceptors. Some organs appear to have specifi c nociceptors, such as the heart, lung, testis, and bile ducts. Most other organs, such as the intestines, are innervated by polymodal nociceptors that respond to smooth muscle spasm, ischemia, and infl ammation. Th ese receptors generally do not respond to the cutting, burning, or crushing that occurs during surgery. Like somatic nociceptors, those in the viscera are the free nerve endings of primary aff erent neurons whose cell bodies lie in the dorsal horn. Th ese aff erent nerve fi bers, however, frequently travel with eff erent sympathetic nerve fi bers to reach the viscera. Aff erent activity from these neurons enters the spinal cord between T1 and L2. Nociceptive C fi bers from the esophagus, larynx, and trachea travel with the vagus nerve to enter the nucleus solitarius in the brainstem. Aff erent pain fi bers from the bladder, prostate, rectum, cervix and urethra, and genitalia are transmitted into the spinal cord via parasympathetic nerves at the level of the S2-S4 nerve roots. Th ough relatively few compared with somatic pain fi bers, fi bers from primary visceral aff erent neurons enter the cord and synapse more diff usely with single fi bers, oft en synapsing with multiple dermatomal levels and oft en crossing to the contralateral dorsal horn.