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AACN Clinical IssuesVolume 16, Number 3, pp. 277–290C© 2005, AACN

The Physiology and Processing of PainA Review

Cynthia L. Renn, RN, PhD, ACNP; Susan G. Dorsey, RN, PhD

Despite the many advances in ourunderstanding of the mechanismsunderlying pain processing, paincontinues to be a major healthcareproblem in the United States. Each day,millions of Americans are affected by bothacute and chronic pain conditions, costingin excess of $100 billion fortreatment-related costs and lost workproductivity. Thus, it is imperative thatbetter treatment strategies be developed.One step toward improving painmanagement is through increasedknowledge of pain physiology. Within thenervous system, there are severalpathways that transmit information aboutpain from the periphery to the brain. Thereis also a network of pathways that carrymodulatory signals from the brain andbrainstem that alter the incoming flow ofpain information. This article provides areview to the physiology and processing ofpain. (KEYWORDS: ascending painpathways, descending modulation, pain,nociceptors)

Congress declared the years of 2000 to 2010as the Decade of Pain Control and Research,yet pain continues to be a leading publichealth and nursing problem in the UnitedStates.1 Pain is the principal symptom caus-ing patients to seek medical attention, affect-ing 1 in 5 Americans on any given day.2,3

It is estimated that pain accounts for 1 in

6 visits to a healthcare provider4 and theAmerican Academy of Pain Managementreports5 that uncontrolled pain is at epidemicproportions, with 50 million Americans suf-fering from some form of chronic pain andanother 25 million experiencing acute paincaused by accident or surgical procedureseach year. Studies6–8 estimate that 70 millionvisits to healthcare providers were motivatedby pain and that 4.9 million people visited ahealthcare provider for treatment of chronicpain, all at an estimated cost exceeding $100billion. Further, pain patients and their fami-lies suffer from intangible costs related to thepain, such as decreased quality of life, de-pression, and interpersonal stresses.9

Pain not only affects patients and theirfamilies, but also society and the economyas well. Beyond the cost of medical treat-ment, society bears the costs of increasedhealthcare utilization and lost productivityby patients in pain. More than two thirdsof those living with chronic pain have hadtheir pain for 5 or more years, often pro-ducing significant limitations on daily activ-ity, and it is estimated that 36 million Amer-icans missed nearly 4 billion work days dueto pain, resulting in a substantial loss of work

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From the Department of Organizational Systems andAdult Health, School of Nursing, University of Maryland,Baltimore, Maryland.

Reprint requests to Cynthia L. Renn, Assistant Profes-sor, University of Maryland School of Nursing, Depart-ment of Organizational Systems and Adult Health, 3rdFloor, 655 West Lombard Street, Baltimore, MD 21201–1579 ([email protected] ).

277

278 � RENN AND DORSEY AACN Clinical Issues

productivity and an estimated cost of $65 bil-lion annually.7

A critical step toward minimizing the phys-ical, emotional, and financial drain on pa-tients and caregivers is improving the clin-ical management of pain. When managingthe care of a patient with pain, the advancedpractice nurse must work together with thepatient to establish a common treatment goal.In many cases, the goal of the treatment strat-egy may be to achieve maximal analgesia(the absence of a pain response to a nox-ious stimulus).10,11 However, when maximalanalgesia is not possible, the treatment goalshifts to reducing the pain to a level that thepatient finds tolerable and allows for the per-formance of normal activities of daily living.Upon establishment of the treatment goal, thenext step is to develop a plan to meet thatgoal. A key factor that aids in the processof selecting the most appropriate treatmentmodalities, in addition to a thorough painassessment, is an in-depth understanding ofpain physiology. A thorough understandingof how pain is processed at each stage inthe peripheral and the central nervous sys-tems allows the treatment strategy to be tai-lored to meet the needs of the individualpatient. This article provides a primer on ma-jor structures and processes involved in painphysiology.

� What Is Pain?

When a region of the body is exposedto a tissue-damaging or potentially tissue-damaging insult, one experiences the un-pleasant sensation of pain.12 Pain has beendescribed as a multifaceted and highly sub-jective experience that is unique to eachperson. Pain is not only influenced by phys-iological processes, but also influenced bypsychological and emotional processes aswell. It has been reported that the inten-sity of pain can be influenced by contex-tual cues. For example, similar types of trau-matic injury may be seemingly painless incertain situations and extremely painful inothers.13,14 This phenomenon was first de-scribed by Beecher,13 who found that soldierswith severe wounds often reported little painwhile civilians with similar injuries typicallyreported severe pain. The subjective nature

of the pain experience led McCafferey15 todefine pain as “whatever the experiencingperson says it is, existing whenever the ex-periencing person says it does.”(p7) Pain hasfurther been defined by the International As-sociation for the Study of Pain (IASP)10 as“an unpleasant sensory and emotional expe-rience associated with actual or potential tis-sue damage or described in terms of suchdamage.”(p250)

Two broad categories of pain, acute andchronic, are seen in the clinical setting. Un-der these broad categories fall the subtypesof pain, which include inflammatory, neuro-pathic, cancer, etc. Acute pain tends to be ofa short duration, typically has an identifiablecause, and is focal to the site of injury.10–13,16

Further, acute pain functions as an endoge-nous protective mechanism that signals thebrain of the occurrence of real or poten-tial tissue injury, thus prompting a protectiveresponse.12 Clinically, acute pain functions asa symptom, tends to be self-limited, and gen-erally responds to a straightforward treatmentplan with a good to excellent prognosis.16

However, pain can persist beyond the pointof tissue healing and develop into a chronicand debilitating state. Chronic pain is unre-lenting, has no identifiable cause, spreads be-yond the original site of injury, and serves nobiological function.10–13,16 Clinically, chronicpain has the characteristics of a disease state,can produce psychological disturbances, re-quires complex treatment strategies, and typ-ically has a poor prognosis.16

� Pain Transmission: The AscendingPain Pathways

The ascending pain pathways transmit noci-ceptive information from peripheral tissues tothe cerebral cortex for interpretation as pain.The ascending pathways are complex struc-tures, involving both the peripheral (PNS)and central nervous systems (CNS).

Nociception

Nociception, the initial processing of pain,involves a system of mechanisms that en-code and transmit the pain signal, along theascending pathway, from the point of nox-ious stimulation in the periphery to higher

Vol. 16, No. 3, July-Sept 2005 PAIN PROCESSING � 279

Figure 1. Ascending painpathway. The ascending painpathway transmits nociceptiveinformation from peripheraltissues (1) via a primary afferentnerve fiber, which enters thespinal cord in the dorsal horn(2) where it synapses witha second-order neuron. Thesecond-order neuron travels upthrough the spinal cord (3) andbrainstem, synapsing in the tha-lamus with a third-order neuronthat transmits the nociceptiveinformation to the brain (4) forinterpretation as pain. Adaptedwith permission from Fields andBasbaum.63(p310)

centers in the CNS, including the cerebralcortex where an awareness of the presenceof pain occurs12 (see Figure 1). The firststep in the complex pain process is thetransduction of a noxious stimulus (nocicep-tion) by specialized nerves (nociceptors).17,18

Nociceptors are found in most organs andtissues in the body and are activated by ei-ther a noxious mechanical (touch or pres-sure), thermal (hot or cold), or chemical (en-dogenous or exogenous) stimulus12,17,18 (seeFigure 2). The term noxious is appliedto nociceptive stimuli because nociceptorsare activated in response to strong stim-uli that fall in the tissue-damaging range,whereas nonnociceptive mechanoreceptors,thermoreceptors, and chemoreceptors re-spond to milder stimuli that fall in a rangebelow the tissue-damaging level.12,17,18 In ad-dition to exogenous chemicals that stimulate

nociceptors, a number of endogenous chemi-cals have been identified that can activate no-ciceptors, including potassium, bradykinin,serotonin, histamine, prostaglandins, andothers.19–23

Spinal Dorsal Horn

When a noxious stimulus is transduced by anociceptor, a signal is generated that is trans-mitted as an electrical action potential alongsmall diameter A-delta (myelinated, fasttransmission, sharp or pricking first pain)24,25

and C (unmyelinated, slow transmission, dullor burning second pain)25,26 primary affer-ent nerve fibers to the gray matter of thespinal cord (see Figure 2 inset). On cross-section, the spinal gray matter forms a but-terfly shape and can be divided into 10 lami-nae, or layers, which are numbered I through


Figure 2. Pain transmission from peripheral tissues to the spinal cord. Noxious stimuli (thermal, chemical, ormechanical) that are applied to peripheral tissues activate nociceptors that are located within the tissues. Thestimulus is transduced by the nociceptor to generate a nociceptive signal that is transmitted as an action potentialalong a primary afferent nerve to the dorsal horn of the spinal cord. Within the primary afferent nerve (inset), thesignal can be transmitted rapidly by myelinated A-delta fibers or more slowly by unmyelinated C fibers. The dorsalroot ganglion is part of the primary afferent nerve, located near the spinal cord, and contains the cell bodies of allfibers traveling within the nerve.

IX, from dorsal to ventral, with X surround-ing the central canal18,27,28 (see Figure 3).Pain processing occurs predominantly inlaminae I, II, and V.18,28

The primary afferent fibers enter the spinalcord in the dorsolateral aspect of the graymatter (the dorsal horn) through the dorsalroot. Upon entering the dorsal horn, the pri-mary afferents bifurcate in a “T” pattern andtravel 2 to 3 spinal segments within Lissauer’s

Figure 3. Structure of the spinal cord. The gray matter is a butterfly-shaped area in the center of the spinal cord.The gray matter contains unmyelinated nerve fibers and the cell bodies of the neurons. The spinal gray matter issurrounded by white matter, which is composed of myelinated nerve fibers. The central canal is a conduit for cerebralspinal fluid and runs the full length of the spinal cord. The spinal gray matter has two dorsal and two ventral horns.The dorsal horns, comprising the dorsal aspect of the gray matter bilaterally, are primarily responsible for receivingand transmitting sensory information. The ventral horns, comprising the ventral aspect of the gray matter bilaterally,are primarily responsible for sending motor information out to the periphery. Based on cellular organization, the graymatter can be divided into ten laminae (layers), which are numbered I-IX from dorsal to ventral. Lamina X surroundsthe central canal.

tract in both the rostral (toward the nose) andcaudal (toward the tail) directions. As the pri-mary afferents travel in Lissauer’s tract, theysend collateral projections to the gray matteralong the entire 4 to 6 segment length,12,29,30

thus transmitting the pain signal over a broadarea of the spinal cord rather than to a dis-crete location (see Figure 4). This is impor-tant in the case of spinal pathology, such asa lesion, which could block the signal if it is


Figure 4. Lissauer’s tract and primary afferent collat-eralization in the spinal cord. The primary afferent fiber(PAF) enters the spinal dorsal horn and the nerve fibersbifurcate in Lissauer’s tract. After bifurcation, the nervefibers travel 2–3 spinal segments in both the rostral andcaudal directions. Throughout the length of travel in Lis-sauer’s tract, the afferent nerve fibers send out collat-eral projections into the dorsal horn to transmit the painsignal across multiple segments of the spinal cord.

transmitted to a discrete location within thearea of pathology.

In the dorsal horn, the primary afferentfibers synapse (connect), either directly or in-directly (via interneurons), with second-orderprojection neurons and convey the nocicep-tive message through the release of a vari-ety of neurotransmitters, such as the exci-tatory amino acid glutamate or the peptidesubstance P12,31,32,33 (see Figure 5). After thenociceptive signal has been received in thedorsal horn, the information is transmittedto higher centers in the CNS by projectionneurons.17,18,34,35

Ascending Tracts

The projection neurons transmit the noci-ceptive signal rostrally along the ascend-ing pathways in the spinal cord to vari-ous supraspinal structures in the brainstemand diencephalon, including the medullaryreticular formation, periaqueductal gray,parabrachial region, hypothalamus, thala-mus, and various limbic structures.17,18,34,35

The function of the ascending pathways issimply the transmission of the nociceptiveinformation. Within the supraspinal targetstructures of the ascending pathways, third-

order neurons further process the nocicep-tive signal and transmit it to cortical and lim-bic structures, where the signal is interpretedas pain.12

The organization of and the neuroanatomywithin the ascending pain pathways are quitecomplex.17,18,34,35 The most prominent andwell-described of the ascending pathwaysis the spinothalamic tract (STT—spinal cordto thalamus), which is thought to trans-mit sensations of pain, temperature, andtouch.12,17,18 The majority of the projectionneurons that travel in the STT originate inthe superficial laminae I and II and deeperlamina V of the spinal dorsal horn.36,37 Be-fore ascending, the STT neurons decussate(cross midline) through the ventral whitecommissure (junction between two parts) tothe opposite ventrolateral quadrant of thespinal cord white matter, where they ascendin the ventrolateral funiculus (VLF—bundleof nerve fibers) to the thalamus12,36,37 (seeFigure 6a). A second prominent ascendingpathway that is involved in pain transmis-sion is the spinomesencephalic tract (SMT—spinal cord to mesencephalon), which origi-nates in laminae I, II, and V of the spinal dor-sal horn, decussates, and also travels in theVLF to the mesencephalon (also known asthe midbrain)12,36,38,39 (see Figure 6b). Withinthe midbrain, the neurons in the SMT termi-nate in several areas, such as the periaque-ductal gray (PAG) and nucleus cuneiformis,among others.18,39–41 A third tract that hasalso been shown to convey nociceptive in-formation is the spinoreticular tract (SRT—spinal cord to reticular formation), whichterminates in the reticular formation of themedulla12,17,18 (see Figure 6c). Though eachascending tract has a primary target structure,they also send collateral projections to otherareas of the brainstem as they pass through.When the projections from the spinal cordreach their targets, they synapse with third-order neurons that serve as relays and projectto other regions within the brainstem, dien-cephalons, and forebrain.12,17 While the threepathways described above are thought tobe the predominant pathways involved inpain transmission, they do not constitute acomplete list of all ascending sensory path-ways. A detailed description of the remain-ing pathways is beyond the scope of thisreview.


Figure 5. Synapse of the primary afferent fiber with a projection neuron in the dorsal horn. The primary afferentfiber (PAF) enters the spinal dorsal horn and synapses (A) directly with a projection neuron (PN; second-orderneuron) or (B) with an interneuron (IN) that then synapses with a projection neuron. The pain signal is transmittedacross the synapse by the release of neurotransmitters from the presynaptic neuron that cross the synaptic cleftand bind with receptors on the postsynaptic neuron.

ThalamusThe thalamus is thought of as the majorsupraspinal relay structure for the integration

Figure 6. Ascending transmission tracts. (A) Spinothalamic tract (STT). The projection neurons that form the STToriginate predominantly in laminae I, II, and V of the spinal dorsal horn. The STT neurons decussate (cross midline)through the ventral white commissure to the opposite ventrolateral quadrant of the spinal cord. In the ventrolateralquadrant, the STT neurons ascend from the spinal cord to the thalamus in the ventrolateral funiculus (VLF; bundleof fibers). (B) Spinomesencephalic tract (SMT). The neurons that form the SMT also originate predominantly inlaminae I, II, and V of the dorsal horn. The SMT neurons decussate through the ventral white commissure to theVLF, where they ascend from the spinal cord to the mesencephalon and terminate in several structures such as theperiaqueductal gray (PAG). (C) Spinoreticular tract (SRT). The SRT neurons originate predominantly in laminae I,II, and V of the dorsal horn, decussate through the ventral white commissure to the VLF and ascend from the spinalcord to the reticular formation of the medulla. Adapted with permission from Fields and Basbaum.63(p310)

and transfer of ascending nociceptive infor-mation to the cerebral cortex.18,42 As such,the thalamus not only receives input from the


STT, but it also receives input from collateralprojections sent out of the other ascendingtracts that carry nociceptive information.18,42

Within the thalamus, nociceptive informa-tion regarding the type, temporal pattern in-tensity, and topographic localization of thepain is encoded prior to sending the informa-tion onward to limbic structures and corticalsites.12,18,42

Cerebral Cortex

Ultimately, the nociceptive signal reaches thecerebral cortex where it is integrated and un-dergoes cognitive and emotional interpreta-tion as stemming from a painful stimulus.12,43

The nociceptive signal is transmitted fromthe thalamus to a variety of cortical sites:the somatosensory S1 area and S2 area, theinsular cortex, the anterior cingulate cortex,and the medial prefrontal cortex.44–48 Withinthese cortical regions, there is a complexnetwork of interconnections that include thethalamus and limbic structures.49 This net-work of cortical structures is responsible forthe sensory-discriminative (perception of theintensity, location, duration, temporal pat-tern, and quality of noxious stimuli) andmotivational-affective (relationship betweenpain and mood, attention, coping, tolerance,and rationalization) components of the painexperience.12,50,51

� Descending Modulation ofNociception

The idea that pain undergoes modulatory ef-fects from higher areas of the CNS was firstintroduced by Head and Holmes.52 Over thepast century, a large volume of informationhas been learned regarding pain perceptionand modulation. Thus, much effort has beenput into understanding the mechanisms in-volved in the modulatory process.53–55

Several decades after Head and Holmes52

first theorized that pain is under the influ-ence of higher areas in the CNS, studies con-firmed their theory by providing evidencethat a number of supraspinal sites contributeto the control of ascending sensory inputby exerting tonic inhibitory control of neu-rons in the spinal dorsal horn.56–58 Further

research into the contribution of supraspinalstructures to nociceptive modulation showedthat the mammalian CNS has several well-defined, supraspinally organized descendingpathways. These pathways form a network ofneural systems that modulate the ascendingtransmission of nociceptive information, withthe most well-described being the circuitrymediating the brainstem control of nocicep-tive transmission at the level of the spinal dor-sal horn.53–63

The effects of descending modulationare exerted in the spinal dorsal horn onthe synapse between the primary afferentand projection neurons or on interneuronsthat synapse with projection neurons (seeFigure 7). This synapse in the dorsal hornis the point where nociceptive informationis first integrated before being transmittedto higher centers in the CNS.12,18,54,64 Thedescending modulatory effect is applied ei-ther by inhibiting the release of neurotrans-mitter from the primary afferent fiber (seeFigure 7A) or by inhibiting the functionof neurotransmitter receptors on the post-synaptic neuron (see Figure 7B). Severalsupraspinal sites are known to contributeto the descending modulation of noci-ception, either directly (sending projectionneurons to the spinal cord) or indirectly(sending projection neurons to other re-gions in the brainstem that send projec-tions to the spinal cord). These includethe PAG, locus coeruleus (LC), and therostral ventromedial medulla (RVM) amongothers.12,54,63,65,66

Periaqueductal Gray

The PAG is a midline structure, composed ofdensely packed heterogeneous neurons, thatsurrounds the cerebral aqueduct through-out the mesencephalon67,68 (see Figure 8).It has been well established that the PAGis a major component of the pain modula-tory circuitry, since Reynolds53 first reportedthe phenomenon of stimulation producedanalgesia after performing abdominal surgeryon an unanesthetized rat while electricallystimulating the PAG.59,69 Given that few PAGefferents project directly to the spinal dor-sal horn,70–72 researchers have focused ondiscovering other pathways that mediate the


Figure 7. Effect exerted by a descending modulatory projection neuron on the synapse between a primary afferentfiber and a projection neuron in the dorsal horn. The descending modulatory projection neuron can exert its effectby inhibiting the release of neurotransmitters from the primary afferent fiber (PAF) in the spinal dorsal horn (A)or by inhibiting neurotransmitter receptors on the ascending projection neuron (PN; B), thus altering the flow ofnociceptive information to the brain.

spinal effects of PAG stimulation. It wasfound that the modulatory effect of the PAGis exerted indirectly through efferent connec-tions with a variety of brainstem structures,such as the RVM, parabrachial nucleus, locuscoeruleus, and the A5 and A7 noradrenergiccell groups.73–78

LOCUS COERULEUS: The LC is a bilateral struc-ture, composed of noradrenergic neurons,that is located in the pons on the border ofthe fourth cerebral ventricle79 (see Figure 9).Bilateral projections from the LC and nearbyA7 cell group descend primarily to the con-

Figure 8. The periaqueductal gray (PAG). The PAGis a midline structure that surrounds the cerebral aque-duct in the mesencephalon of the brainstem.

tralateral spinal dorsal horn laminae I, II,and V where they exert an antinociceptiveeffect.79–81 In addition to the intrinsic antinoci-ceptive effects of the pontine noradrener-gic cell groups, they also receive neuronalprojections from the RVM and PAG, thusserving as relays for the modulatory effectsfrom the RVM and PAG to the spinal dorsalhorn.82,83

Rostral Ventromedial Medulla

The RVM has been studied at length andis recognized as a major component of the

Figure 9. The locus coeruleus (LC). The LC is a bi-lateral structure that is adjacent to the fourth ventriclein the pons of the brainstem.


Figure 10. The rostral ven-tromedial medulla (RVM). TheRVM is a region of the ventralmedulla that includes the midlinenucleus raphe magnus (NRM),gigantocellularis pars alpha (GiA)and lateral paragigantocellularis(LPGi).

pain modulatory circuitry, exerting its ownmodulatory effects in addition to relayingthe modulatory effects from higher brainstemsites.54,84,85 It is a large region of the medullathat includes the midline nucleus raphe mag-nus (NRM) and portions of the adjacent retic-ular formation; the nucleus reticularis gigan-tocellularis pars alpha (GiA) and the nucleusparagigantocellularis lateralis (LPGi) (Figure10). Efferent projections from the RVM ex-tend bilaterally, have been identified in alllevels of the spinal cord, and comprise amajor portion of the neurons projecting tothe spinal dorsal horn.61,62,86–90 These neuronshave widely collateralized yet lamina-specificprojections,91 with dense bilateral termina-tions in laminae I, II, and V of the spinalcord dorsal horn.63,92,93 While all of the com-ponents of the descending modulatory net-work are important, the PAG and RVM havebeen shown to play key roles in the under-lying mechanisms of pain modulation.54,63,85

Further, the PAG to RVM projection is criti-cal for the PAG to exert its descending mod-ulatory effect on dorsal horn nociceptiveneurons.76,84,93,94

The RVM exerts its modulatory effecton nociceptive transmission at the spinallevel, producing antinociception to painfulstimuli.73,74,95 During persistent noxious stim-ulation, such as during a prolonged inflam-matory state, there is continued activation ofthe descending pain modulatory circuitry andincreased neuronal activity in the RVM thatresults in a progressive enhancement of de-scending modulation of spinal nociceptivetransmission.96–102

Biphasic Modulation

The descending modulation of nociceptionis not wholly inhibitory. Several lines of ev-

idence demonstrate time-dependent bipha-sic properties of the pain modulatory systemthat can both inhibit and facilitate nocicep-tive transmission.97,100,103–108 However, manyaspects of the underlying mechanisms of no-ciceptive modulation and the shift from facil-itation to inhibition remain unclear.

The RVM is one area in the pain mod-ulatory system that puts forth opposingmodulatory effects and is a crucial sitefor balancing descending modulation. Whenactivating the descending pathways that orig-inate in the RVM, the resulting effect (in-hibitory or facilitatory) is dependent onthe intensity and nature of the intra-RVMstimulus.106–108 Although the circuitry respon-sible for generating facilitatory and inhibitorymodulation may be distinct, an anatom-ical and neurochemical differentiation ofthe bimodal modulatory structures has notbeen determined.97,103,104,106,109 However, sev-eral studies that used either electrical stimula-tion or lesions have shown opposing modu-latory effects from the different subregions ofthe RVM.107,109,110 The effects of both descend-ing inhibition and facilitation have been ob-served during multineuron recording in thedorsal horn, where it has been shown thatneighboring neurons are simultaneously un-der facilitatory and inhibitory control fromsupraspinal structures.111 The balance be-tween inhibition and facilitation determinesthe net effect of descending modulation onnociceptive transmission.18,34,110,112

In summary, the processing of pain is acomplex phenomenon, involving both theperipheral and central nervous systems. No-ciceptive information regarding actual or po-tential tissue injury is transmitted from pe-ripheral nerve endings (nociceptors), via acomplex series of ascending pathways, tothe brain. Within the brain, the nociceptive


signals are further processed in the so-matosensory cortex and interpreted as pain.As the ascending nociceptive informationpasses through the brainstem and reachesthe brain, it triggers the activation of a net-work of brainstem structures and pathwaysthat exert a modulatory effect on nociceptivetransmission. The structures involved in painmodulation send neuron projections from thebrainstem to the spinal dorsal horn wheretheir modulatory effect alters the transfer ofnociceptive information from the primary af-ferent to the second-order neuron. Thus, theflow of further nociceptive information fromthe periphery is either inhibited (resulting inless pain) or facilitated (resulting in morepain).

� Clinical Significance

New scientific discoveries that stem from re-search into the mechanisms that underliepain can lead to the development of newtreatment strategies for managing patientswith pain, whether acute or chronic. For ex-ample, it is known that nonsteroidal anti-inflammatory drugs (NSAIDs) block the syn-thesis of prostaglandins, which play a rolein the sensitization of nociceptors, thus de-creasing pain from inflammation. However,prostaglandins do not act alone. There aremany other endogenous substances (inflam-matory mediators) that can sensitize noci-ceptors, such as bradykinin, serotonin, cy-tokines, and others. Therefore, pain researchcan lead to the development of new pharma-cological agents that are directed against theactions of these sensitizing substances andprovide new avenues of pain management.113

Our understanding of the mechanisms un-derlying pain and endogenous modulation isincreasing, and many targets exist along thepain pathways for intervention in the treat-ment of pain. Pain transmission can be inter-rupted in the periphery by giving drugs thatblock sensitization of nociceptors (NSAIDs)or by blocking nerve transmission (lidocaineinjection into a peripheral nerve). Pain per-ception can also be altered by giving drugsthat work in the CNS (opioids). By gaining in-creased knowledge of the how the pain pro-cessing system works, the advanced practicenurse will be better able to design a treatment

plan that is appropriate for each individualpatient.

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