Pathophysiologycal aproach

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CLINICAL REVIEWS Management of pain

1531Am J Health-Syst Pharm—Vol 72 Sep 15, 2015

C L I N I C A L R E V I E W S

Pathophysiology, assessment, and managementof pain in critically ill adults

DAVID P. R EARDON, KEVIN E. ANGER , AND PAUL M. SZUMITA

DAVID P. R EARDON, PHARM.D., BCPS, is Multispecialty Care ClinicalPharmacist, Department of Pharmacy, Yale–New Haven Hospital,New Haven, CT. KEVIN E.ANGER , PHARM.D., BCPS, is Clinical Phar-macy Specialist—Critical Care; and PAUL M. SZUMITA, PHARM.D.,BCPS, is Clinical Pharmacy Practice Manager, Department of Phar-macy, Brigham and Women’s Hospital, Boston, MA.

Purpose. The pathophysiology of pain in

critically ill patients, the role of pain assess-

ment in optimal pain management, and

pharmacologic and nonpharmacologic

strategies for pain prevention and treat-

ment are reviewed.

Summary. There are many short- and long-

term consequences of inadequately treat-

ed pain, including hyperglycemia, insulin

resistance, an increased risk of infection,

decreased patient comfort and satisfac-

tion, and the development of chronic pain.

Clinicians should have an understanding

of the basic physiology of pain and the

patient populations that are affected. Pain

should be assessed using validated pain

scales that are appropriate for the patient’s

communication status. Opioids are the

cornerstone of pain treatment. The use

of opioids, administered via bolus dosing

or continuous infusion, should be guided

by patient-specific goals of care in order

Address correspondence to Dr. Reardon ([email protected]).The authors have declared no potential conflicts of interest.

Copyright © 2015, American Society of Health-System Pharma-cists, Inc. All rights reserved. 1079-2082/15/0902-1531.

DOI 10.2146/ajhp140541

to avoid adverse events. A multimodal

approach to pain management, including

the use of regional analgesia, may improve

patient outcomes and decrease opioid-

related adverse events, though there are

limited relevant data in adult critically ill

patient populations. Nonpharmacologic

strategies have been shown to be effec-

tive adjuncts to pharmacologic regimens

that can improve patient-reported pain

intensity and reduce analgesic require-

ments. Analgesic regimens need to take

into account patient-specific factors and be

closely monitored for safety and efficacy.

Conclusion. Acute pain management in

the critically ill is a largely underassessed

and undertreated area of critical care.

Opioids are the cornerstone of treatment,

though a multimodal approach may

improve patient outcomes and decrease

opioid-related adverse events.

Am J Health-Syst Pharm. 2015; 72:1531-43

Pain occurs in nearly half of allhospitalized intensive care unit(ICU) patients, with a large

proportion of those patients report-ing dissatisfaction with their paincontrol.1 Critical care practitionersneed to have an understanding ofpain and pain management because,despite growing evidence of pain andits long-term consequences, there hasbeen little progress in improving thetreatment of acute pain in the last 20

years.2 Pain has been shown to be amajor stressor in the ICU, and chron-ic pain is a major sequela of critical

illness, as reported by nearly half ofthe survivors of an ICU episode.3,4 Optimal management of pain incritically ill patients requires knowl-edge of pain physiology and etiology,appropriate assessment tools for dif-ferent patient populations, and phar-macologic and nonpharmacologictreatment strategies. It should bethe goal of healthcare practitionersto assess and treat pain to preventsuffering and provide comfort forpatients.5,6

The aim of this article is to re-view the pathophysiology of pain incritically ill patients, the role of painassessment in optimal pain manage-ment, and pharmacologic and non-

pharmacologic strategies for painprevention and treatment.

Overview of pain

Pain physiology. The Internation-al Association for the Study of Painhas defined pain as “an unpleasantsensory and emotional experienceassociated with actual or potentialtissue damage, or described in terms

of such damage.”7 Pain is a subjectiveexperience; there are no objectivemeans of measuring the degree orseverity of pain, with patient reportsbeing the most accurate and reliableindicators.8 Pain and its severity donot necessarily reflect tissue damageor its extent, and tissue damage mayoccur in the absence of pain. Mostcommonly, acute pain is the physi-


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1532 Am J Health-Syst Pharm—Vol 72 Sep 15, 2015

ologic and psychological response tonociception.

Nociception is the transfer ofinformation from a location of tis-sue damage to the central nervous

system. Nociceptors are primarilynonspecific free endings of afferentnerve fibers that act as sensory recep-tors specializing in perceiving tissuetrauma from chemical, thermal, andmechanical sources.9 Nociceptors arepresent in the skin, subcutaneoustissue, bone, muscle, and viscera. Onexposure to a noxious stimulus, anerve impulse is generated (a processcalled transduction) and transmittedto the spinal cord and brain from

the point of transduction or tissueinjury. The signal is then perceived inhigher structures, such as the corti-cal and limbic systems, to be pain.After perception, modulation (theinhibition or facilitation of inputfrom the brain) influences furthernociception.

During transduction, tissue dam-age and breakdown cause the re-lease of inflammatory intracellularmediators such as prostaglandins,substance P, bradykinin, histamine,serotonin, and other cytokines.10 Thisrelease is responsible for the genera-tion of a nerve impulse and the sen-sitization of other nociceptors, whichincreases their excitability. Nerve im-pulses travel along nerve axons to thedorsal horn of the spinal cord, wherethey cause the release of excitatoryand inhibitory neurotransmitterssuch as glutamate, aspartate, andγ -aminobutyric acid (GABA) andneuropeptides such as substance P

and endogenous opioids. Excitatoryneurotransmitters and substanceP forward the nociceptive impulseto the brain, while the inhibitoryneurotransmitters and endogenousopioids are responsible for inhibi-tion of nociceptive transmission. Inthe setting of peripheral inflamma-tion, there is upregulation of dorsalhorn neuronal receptor expressionin transmitters of primary sensoryor nociceptive neurons as well as a

decrease in transmission inhibition,which may facilitate further paintransmission.11

Nociception and pain are furtherdelineated on the basis of the ana-

tomical location and the perceivedresponse to noxious stimuli. Somat-ic nociception originates in periph-eral tissues and is characterized bya sharp stabbing pain or a localizeddull ache. In comparison, visceralnociception originates in organsand can be described as cramping,paroxysmal, and difficult to localize.Another type of pain, neuropathicpain, is caused by disorders of theperipheral and central nervous sys-

tems and results in the perception ofpain without nociception or tissueinjury.12

Peripheral neuropathic pain re-sults from lesions caused by trauma,metabolic disease, infection, tumorinvasion, or neurotoxins and leadsto continuous, inappropriate trans-duction and transmission of nerveimpulses and, in rare circumstances,the development of complex regionalpain syndrome.13 Central neuro-pathic pain is most commonly theresult of stroke, spinal cord injury, ordemyelinating diseases such as mul-tiple sclerosis.14

There are multiple patient-specificfactors that may influence the per-ception of pain. Patients with chronicpain, including an estimated 70million Americans, may experiencemarkedly increased pain perceptionrelative to patients without chronicpain at baseline.15,16 Women are morelikely than men to experience pain

and also have a lower pain thresh-old.17 Relative to younger patients,elderly patients are more likely tohave a slower response to pain andto report pain as burning or achingrather than sharp or stabbing. Pa-tients with baseline depression aremore likely to experience pain thanthose without baseline depression.18 Changes in cognition with increasedage may alter patients’ ability to com-municate pain, and pain in elderly

patients may manifest atypically informs such as delirium.19

The use of i.v. sedatives has beenshown to alter the perception ofpain. Midazolam has been shown

to increase the perception of heat,cold, and electrical pain.20 Propofolhas been shown to decrease painassociated with ischemia, while dex-medetomidine can reduce cold andischemic pain. It is clinically impera-tive to assess for medications thatmay alter the perception of pain andminimize patient exposure wheneverfeasible.

Epidemiology and outcomes.Approximately 50% of all critically

ill patients experience moderate-to-severe pain during an ICU stay,with little difference in this regardbetween surgical or trauma patientsand medical patients.21 It is impor-tant to note that studies quantifyingpain in the ICU focus on moderate-to-severe pain as their endpoint.There are many risk factors for painamong critically ill patients in theICU. To our knowledge, a compre-hensive list of such risk factors hasnot been established, but pain typi-cally results from the primary diseaseprocess; invasive procedures such asplacement of i.v. lines, fine needleaspirations, biopsies, endotrachealtube suctioning, and mechanicalventilation; peripheral administra-tion of certain medications; mobili-zation of patients; and tissue injuryfrom burns, trauma, or surgery.22,23 In a multivariate analysis, the pro-cedure type, opioid administrationprior to the procedure, pain intensity

and level of pain distress prior to theprocedure, pain intensity within the24 hours prior to the procedure, andwhether or not a nurse performedthe procedure were all independentlyassociated with the likelihood of pro-cedural pain.24

Pain that is not recognized andtreated can have a significant nega-tive impact on patient outcomes.In response to the stress createdby pain, catecholamines, cortisol,


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and glucagon are released. If leftunabated, these hormones can leadto tachycardia, hypertension, an in-crease in myocardial oxygen demand,hyperglycemia and insulin resistance,

and alteration in fat and protein me-tabolism. Stress associated with inad-equately treated pain can also lead tocoagulopathies and reduced activityof the innate and adaptive immunesystems.25,26 Sustained painful stimulican result in hyperalgesia and spinalsensitization, a heightened sensitiv-ity to pain by spinal neurons, whichcan result in an increased responseto minimally noxious stimuli or thetransmission of pain without painful

stimuli, leading to chronic pain.

12,27-29

Assessment of pain

The Society of Critical Care Medi-cine (SCCM) and the AmericanAcademy of Critical Care Nursingcurrently recommend routine as-sessment of pain in all adult ICUpatients.30,31 Pain can occur in criti-cally ill patients not only in responseto noxious stimuli but also duringtimes of rest, so assessment andclear documentation should occuron a scheduled basis multiple timesper day and be incorporated intoinstitutional policies and informa-tion systems.21,32 Although specificrecommendations for the frequencyof assessment are lacking, it is clini-cally prudent to assess pain prior toand after the administration of anal-gesics and with any change in patientcondition. The incorporation of painassessment into a protocol has beenshown to decrease the occurrence of

unacceptable pain and increase thelikelihood of appropriate treatmentof patients in pain.33,34 Systematicevaluation and treatment of pain andagitation in the ICU have also beenshown to decrease the frequenciesof pain and agitation and reduce theduration of mechanical ventilation,the ICU length of stay, and the fre-quency of nosocomial infections.35,36 The guidelines also endorse the useof the Behavioral Pain Scale (BPS)

and the Critical-Care Pain Observa-tion Tool (CPOT) as the most validand reliable options for pain assess-ment in adult critically ill patientswho are unable to self-report.30

Patient reports and assessmentsof pain are the most valid and reli-able measurements and should be theprimary means of assessment whenfeasible.37,38 Two patient self-reportingscales, the Visual Analog Scale (VAS)and the Numeric Rating Scale, havebeen used in clinical practice for many

years. Their use requires that a patientreport, either along a spectrum of “nopain” to “worst pain imaginable” or ona numeric scale of 0–10, the severity of

pain. Both scales have been validatedand should be considered primarymeans of pain assessment if patientsare able to participate.39

Barriers to patient self-reportingare common in the ICU and include(but are not limited to) language bar-riers, altered mental status, sedativeand other medication use, and theuse of both invasive and noninvasivemechanical ventilation.40 In com-municative patients, Puntillo andcolleagues41 were able to correlatea number of behavioral and physi-ologic indicators to the intensityof pain. Nurse assessments of painintensity were compared with patientself-reports and though nursing as-sessments were generally lower, therewas no significant difference. Chang-es in facial expressions, body move-ment, vocalization, and muscle rigid-ity have also been found to be validindicators of pain in ICU patientsrecovering from brain surgery.42

Painful stimuli, such as endotrachealsuctioning, have also been shownto cause changes in upper facial ex-pressions and pupillary reflexes cor-relating with patients experiencingpain.43,44 Vital signs alone have beenshown to be poor diagnostic indica-tors of pain, though acute changesshould prompt evaluation with avalidated pain assessment tool.30,42

The BPS was developed to allowpain assessment based on facial ex-

pression, upper limb movement, andmechanical ventilator compliance. Abedside practitioner evaluates andscores each of these components ona scale of 1–4 to produce a composite

score of 3–12. A score of 5 or higherindicates pain, and higher scoresdenote an increase in pain inten-sity (the BPS intensity assessment re-quires further validation before it canbe adopted for widespread clinicaluse). The BPS was initially validatedin 30 mechanically ventilated traumaand postoperative patients who wereassessed a median of three times eachthrough the use of nociceptive andnon-nociceptive procedures.45 Each

patient was assessed both at rest andduring a nociceptive procedure. Theinvestigators found that the use ofthe BPS in sedated, mechanicallyventilated patients can validly and re-liably measure pain expression. TheBPS was further studied in a widerarray of patient populations, includ-ing medical, surgical, neuroscience,emergency, and general ICUs. The re-sults of the studies further validatedthe BPS for use in noncommunica-tive critically ill patients.46-48

The CPOT takes into account fourbehavioral categories associated withpain: facial expression, body move-ments, muscle tension, and ventilatorcompliance (for intubated patients)or vocalization (for extubated pa-tients). Similar to the BPS scoringmethod, each component is scored,with a possible score of 0–2 and a to-tal score of 0–8. A score of 3 or higherrepresents pain; higher scores do notnecessarily denote an increase in pain

intensity (as with the BPS).30 TheCPOT was validated in a study of 117cardiac surgery patients, includingboth communicative and noncom-municative patients.49 The CPOTscore increased in accordance witha patient’s self-reported pain scoreand was also elevated during pain-ful procedures as opposed to whenpatients were at rest. The results wererevalidated in two studies designedto replicate the above findings. The


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CPOT was assessed in postoperativecardiac surgery patients and showeda significant difference in scores be-tween noxious and nonnoxious pro-cedures.50,51 To expand the validity of

this test to other critically ill patientpopulations, the CPOT has beenevaluated in brain-injured patients,patients in a neurosurgery ICU, and ageneral population of adult criticallyill patients.52-55

There are several limitations to thecurrently available behavior-basedpain assessment tools. In patientswith brain injury, altered levels ofconsciousness, cognitive defects, ordelirium, there may be changes in

behavioral responses to pain thatmake it difficult to assess pain usingthese scales. Language and culturaldifferences may also influence behav-ioral responses to pain, complicating

interpretation of pain scale scores.56

Although the BPS and CPOT havebeen validated in numerous patientpopulations, continued rigorous test-ing in specific patient populationsis warranted and ongoing. Table 1summarizes the relevant clinical dif-ferences between the two scales.49-56

The use of validated assessmenttools should be a focus of all insti-tutions incorporating educationalefforts to train staff on their use

and role in therapy.57 Implementa-tion strategies should focus on theoptimal uptake of the assessment, asit has a large impact on the decision-making process for pain manage-

ment.58

Once implemented, assess-ment tools, particularly the CPOT,have been shown by clinical staff tobe easy to use and understand anduseful in clinical practice as they stan-dardized the approach to patient careand provided a common language.59 Healthcare workers have been shownto vary widely in their perception ofpain, and validated assessment effortscan help minimize that variability.60 Once pain has been assessed and doc-

• Requires assessing ventilator parameters and

patient’s face and body at the same time

• Assesses only 3 domains (facial, ventilator/

vocalization, upper limb movements)

• Higher scores may indicate higher levels

of discomfort, but pain intensity is not

validated; therefore, BPS measures thepresence of pain but not the pain intensity

• Questionable specificity for detection of pain

in the noncommunicative patient

• Not validated in patients unable to move

spontaneously due to neuromuscular

disorder

• Cannot distinguish between pain types

• Reported as being more complex than BPS

• Higher scores may indicate higher levels

of discomfort, but pain intensity is not

validated; therefore, CPOT measures the

presence of pain and not the pain intensity

• Not validated in patients unable to movespontaneously due to neuromuscular

disorder

• Cannot distinguish between pain types

Table 1.

Comparison of Pain Scales49-56

Assessment Tool Advantages Disadvantages

Behavioral Pain Scale (BPS)

Critical-Care Pain Observation

Tool (CPOT)

• Excellent interrater reliability

• Excellent internal consistency (reliability)

• Validated in intubated and nonintubated

patients

• Good responsiveness to stimuli (presence

or absence of pain)

• Validated in medical and surgical criticallyill adult patients

• Recently validated in neurologically

critically ill adult patients

• Excellent interrater reliability

• Excellent internal consistency (reliability)

• Validated in intubated and nonintubated

patients

• Good responsiveness to stimuli (presence

or absence of pain)• Assesses 4 domains (facial, breathing/

ventilator, body movement, muscle

tension)

• Assessment of ventilator domain is based

on ventilator alarms, minimizing subjective

assessment of ventilator compliance

• May be more specific than BPS in the

noncommunicative patient

• Validated in medical, surgical, and critically

ill adult patients

• Preliminary validation in neurologically

critically ill adult patients


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umented, it needs to be appropriatelytreated and monitored.

Management of pain

Principles of pain management.

In all critically ill patients, a “pain-first” approach should generally beadopted, as pain may be a majorcontributory factor in both agitationand delirium.30 In patients receivingneuromuscular blocking agents andin patients with status epilepticusor intracerebral hypertension, painshould be assessed and managed ascircumstances permit, with a focuson the management of appropriatepatient-specific, objective goals (i.e.,

improved Bispectral Index score, im-proved electroencephalography find-ings, reduced intracranial pressure).Pain management should focus onalleviating pain and providing patientcomfort, though it may not be possi-ble to achieve a pain-free state withoutcausing treatment-related adverse ef-fects. Therefore, the treatment of painshould focus on moderate and severepain, with an acceptance that patientsmay experience mild pain.61

Pain management encompassestwo distinct strategies: preventive,or preemptive, management andtreatment of pain. Preventive painmanagement focuses on impedimentof pain transduction and transmis-sion, thereby negating any percep-tion of pain, and attempts to provideanalgesic therapy prior to exposinga patient to known noxious stimuli,thus reducing pain intensity. Treat-ment of pain aims to ameliorate painor lessen its intensity in patients who

are already experiencing pain.Historically, pain has been man-

aged in a reactionary way by givinganalgesics to patients once they beginexperiencing pain. In patients requir-ing significant intervention for painmanagement and those in whomassessment is not feasible, a continu-ous analgesic infusion has been usedas a way to treat current pain and,possibly, prevent further pain. Thisapproach has led to patients expe-

riencing an increased frequency ofsevere pain, with a higher likelihoodof sequelae. In contrast, adminis-tering analgesics prior to a patientexperiencing pain has been shown

to improve treatment efficacy andpatient comfort.62

In surgical patients, preoperativeresponse to noxious stimuli has beenshown to be predictive of early post-operative pain severity.63 Since theseverity of early postoperative painhas been linked to the developmentof chronic pain, there is a role forassessing patients preoperatively forthe risk of experiencing severe painand, potentially, trying to prevent

it. Several studies highlighted theimportance of anticipating exposureto noxious stimuli and administeringanalgesics as a means of preventingnociception and pain. In a landmarktrial aimed at identifying stimuliassociated with pain, the use of pre-procedural analgesics reduced thelikelihood that a patient would ex-perience pain during a procedure.64 The trial also showed that patientsare more likely to receive preproce-dural analgesics if they have pain atbaseline and emphasized the needfor routine identification of all pa-tients at risk for procedural pain. Byapplying topical lidocaine prior tothe administration of subcutaneouslidocaine for placement of centrallines or invasive procedures, theperception of overall pain, as well aspain from lidocaine injection, can besignificantly reduced.65 Mobilizationand rehabilitation of patients are as-sociated with severe pain and adverse

events; preemptive administration ofanalgesia has in such instances beenshown to decrease the frequency ofsevere pain and adverse events.66 Painassociated with medication infusionmay be reduced by giving medica-tions through central lines, addinglidocaine to the infusion fluid, orfurther diluting fluids given throughperipheral lines.

In patients already experienc-ing pain, the goals of therapy are to

reduce the intensity of pain to thehighest degree possible, prevent fu-ture exacerbations of pain, and mini-mize the adverse effects of analgesicagents. Pain should be assessed and

localized (as circumstances permit)in order to determine its cause andto guide appropriate selection oftreatment. After determining whichstrategy is most appropriate for apatient, both pharmacologic andnonpharmacologic therapies shouldbe considered.

Nonpharmacologic strategies.Nonpharmacologic strategies suchas implementation of a pain man-agement guideline or protocol (with

routine pain assessment), optimiza-tion of patient–ventilator synchrony,caregivers’ use of a soothing voice,preprocedural education, and in-clusion of family members duringprocedures should be considered inall critically ill patients as adjuncts topharmacologic strategies.67 Listeningto music has been associated witha decrease in stress response anddecreased cortisol release from thehypothalamic-pituitary-adrenal axis,resulting in a trend toward decreasedopioid use.68 Nursing-led relaxation,guided imagery, and nurse– andphysician–patient interactions with afocus on information and emotionalsupport have been associated withdecreased pain and anxiety.69 The ad-dition of hypnosis to a pain protocolwas shown to increase the effective-ness of opioid therapy, reduce painintensity and anxiety, and providesignificant psychological benefitsin patients with major burns.70 The

addition of relaxation exercises toopioid therapy prior to chest tube re-moval is associated with a decrease inpain scores, as compared with opioidtherapy alone.71

Pharmacologic strategies. Theideal pharmacologic regimen forthe treatment of pain would havea quick onset of action, provide ef-fective relief of pain, have minimaladverse effects, and improve clinicaloutcomes such as hospital length


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of stay and the occurrence of long-term sequelae.72 As there currentlyis no ideal analgesic agent availablefor all patients and types of pain,currently available agents should be

used cautiously, taking into accountpatient-specific goals, disease states,and changes in pharmacokinet-ics and pharmacodynamics due tocritical illness. “Protocolization” oftreatment strategies has been shownto improve patient outcomes such aspain intensity at rest and quality ofsleep, indicating that a systematic ap-proach to medication administrationafter pain assessment should be fol-lowed.73 A pharmacotherapeutic plan

should be devised for all patientsreceiving an analgesic regimen andshould include reassessment of painintensity scores at scheduled inter-vals and monitoring for analgesicregimen–related adverse effects.

Route of administration is animportant consideration when deter-mining the optimal pharmacologicregimen for critically ill patients.74 Continuous i.v. infusion is a com-mon route of administration ofsedatives and analgesics, althoughthis mode of administration has beenassociated with accumulation ofmedications and prolonged durationof medication effect.75-77 Delayed gas-tric emptying, changes in gastric pHand regional blood flow, and feedingtube–nutrient interactions may de-crease absorption of enteral agents,and the use of vasopressors may de-crease absorption of subcutaneous ortransdermal medications.78 Intrathe-cal and epidural administration are

highly effective and have been shownto provide dose-dependent analgesiceffects, as receptor activation inhibitsneuronal depolarization in the dorsalhorn and transmission of nociceptivesignals; however, there are limiteddata regarding these routes of ad-ministration in critically ill popula-tions. Moreover, access to the intra-thecal and epidural compartments iscomplex, and opioid deposition intoepidural fat and vascular uptake are

much greater with these methods,limiting their applicability.79

In patients able to participate intheir own care, the use of patient-controlled analgesia (PCA) may be

preferred. Just as the patient is thebest reference for ascertaining thelocation and intensity of pain, thepatient is also the best reference fordetermining the adequacy of paintreatment. PCA use allows patientsto administer medication when it isneeded and to maintain a stable levelof analgesia. Due to the high level ofpatient involvement it requires, PCAuse should be limited to patients whohave continuing pain control needs

despite proper bolus therapy and areable to assess their own pain (i.e.,are not sedated or delirious). Painshould still be routinely assessed,particularly around the time of self-administration, and documented toensure efficacy and prevent misuse.

Opioids. Opioids are currently themost commonly prescribed analge-sic in the ICU, with upward of 90%of mechanically ventilated patientsreceiving an opioid during theirstay.75 Opioids exert their analgesicproperties through activation of Gprotein–coupled receptors (GPCRs)that inhibit the release of excitatoryneurotransmitters and inflammatorycellular mediators, impair propaga-tion of nerve signals, and attenuatethe excitability of nociceptors. Allopioid receptor subtypes (µ, δ, andκ ) belong to the GPCR family thatmediates the actions of endogenousand exogenous opioids.80 Opioidagents differ in their affinity for

GPCR subtypes, which (along withagent-specific pharmacokinetics)is responsible for the variability ofpharmacodynamics.

Current guidelines recommendthe use of i.v. opioids as the drugclass of choice for first-line treatmentof nonneuropathic pain in the criti-cally ill.30 Summary data on the i.v.opioids most commonly used in theICU are presented in Table 2.74,81,82 Appropriate opioid selection involves

assessment of many patient-specificfactors, including the presence of or-gan dysfunction, the expected dura-tion of treatment, changes in volumeof distribution, and concomitant

medications.83

Opioids with highervolumes of distribution and in-creased lipophilicity, such as fentanyland sufentanil, may be less appropri-ate for longer durations or in obesepatients due to the potential for drugaccumulation and prolonged dura-tion of action.84 In acute organ dys-function, particularly renal dysfunc-tion, opioids with a renally excretedparent compound or active metabo-lite should be avoided. Morphine

and its several active metabolites arecleared renally and have been shownto accumulate in patients with bothacute and chronic renal dysfunc-tion. Caution should be used whencompromised clearance mechanismsraise the risks of accumulation andconsequent adverse effects.85

When monitoring a patient re-ceiving an opioid-containing an-algesic regimen, clinicians shouldkeep in mind that the level of opi-oid consumption alone has beenshown to be poorly correlated withclinical outcomes and should notbe used to assess the efficacy of ananalgesic regimen.86 Opioid dosinghas no fixed upper limit and shouldbe adjusted to patient-specific re-quirements and symptoms. Routineassessment and documentation ofpatient response and comfort arekey in preventing overmedication,undermedication, and failure totreat pain appropriately.87 A pa-

tient’s baseline opioid use shouldbe taken into account when deter-mining which agent, dose, and fre-quency are most appropriate. In onesmall study, opioid-tolerant patients(n = 29) were reported to experiencemore pain in the first 24 hours aftertotal knee arthroplasty and requiredsignificantly more opioids thanopioid-naive patients.88

When converting a patient froman opioid-containing regimen for


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chronic pain to one that addressesa new acute pain process, extremecaution should be taken. The use ofcommon tables for converting fromone opioid to another or from one

route to another may lead to opioidwithdrawal (from underdosing) oran increase in adverse events (fromoverdosing) due to patient-specificand pharmacokinetic variability.89 When converting from transdermalfentanyl or enteral methadone ther-apy to i.v. opioid therapy, cliniciansmust take into account the prolongedonset and duration of action with i.v.opioids. Although available opioidconversion tables may be helpful in

establishing an initial dosing strategy,more frequent assessment of painscores and adjustment of treatmentregimens may be warranted in orderto ensure optimal pain control whileminimizing adverse events.

Nonopioids. Despite a paucity ofevidence regarding their effects incritically ill patients, nonopioid agents

such as nonsteroidal antiinflamma-tory drugs (NSAIDs), acetamino-phen, low-dose ketamine, GABA-ergic agents, and regional anestheticsshould be considered in an attempt

to decrease opioid consumption,improve analgesic regimen efficacy,and decrease opioid-related adverseeffects (Table 3).30,74,90-94 In cur-rent clinical practice, multimodaltherapy is most commonly used notfor critically ill patients but ratherin patients with less severe illness,those with less organ dysfunction,and those more likely to report theirpain scores.93 Multimodal therapyhas been shown to confer benefits

in critically ill patients by improvingpain intensity scores and reducingopioid needs, the duration of me-chanical ventilation, and opioid-related adverse effects.

I.V. acetaminophen. In ICU pa-tients requiring pain managementafter major surgery, the addition ofi.v. acetaminophen to i.v. meperidine

was demonstrated to significantlyreduce BPS and VAS scores, postop-erative meperidine consumption,mechanical ventilation time, andmeperidine-related adverse effects

such as nausea and vomiting.94

De-spite the limited data supporting theuse of i.v. acetaminophen in differ-ent populations of critically ill adultpatients, that form of therapy mayhave a role in treating patients whowould benefit from multimodal paincontrol but lack the access requiredfor oral or rectal administration.

Ketamine. In a randomized double-blind study of patients admitted tothe surgical ICU after major abdomi-

nal surgery, ketamine was shown todecrease morphine consumptionwhile providing similar pain con-trol at rest and during mobiliza-tion.95 Postoperatively, patients werestarted on morphine sulfate PCAwith a 2-mg loading dose followedby patient-controlled bolus dosesof 1 mg that could be administered

Table 2.

Properties of Opioids Commonly Used in Intensive Care Unit74,81,82,a

OpioidHalf-life

(hr)

aCYP3A4 = cytochrome P-450 isozyme 3A4.bRelative to morphine.

Volume ofDistribution

(L/kg)Mode(s) of

MetabolismActive

Metabolite?I.V. Potency

Ratiob Comments

Morphine

Hydromorphone

Remifentanil

Fentanyl

1.5–5

3

0.05

1.3–3.0

1–5

3

0.35

4–6

Demethylation,

glucuronidation

Glucuronidation

Cleavage by esterases

Demethylation,

metabolism by

CYP3A4

Yes

No

No

Yes

1:1

5:1

20:1

100:1

Active metabolite;

may accumulate in

patients with renal

dysfunction

Causes respiratory

depression; may

be preferred

in patients

with ventilatorasynchrony

Rapid onset and short

duration; may be

preferred for acute

pain management

Avoid with

concomitant

CYP3A4 inhibitor

use or hepatic

dysfunction


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every seven minutes without anylimitation; they were then randomlyassigned to receive a continuous pla-cebo infusion (0.9% sodium chlorideinjection) or low-dose ketamine (a

bolus of 0.5 mg/kg followed by acontinuous infusion of 2 µg/kg/minduring the first 24 hours and 1 µg/kg/min in the next 24 hours). VASscores were assessed during mobi-lization and at rest. There were nodifferences in VAS scores, sedationscores, or adverse events betweenthe two groups, though patients inthe ketamine group required signifi-cantly less morphine than patients inthe placebo group. Other, nonran-

domized studies have found similarketamine-associated decreases inopioid consumption, though ratesof adverse events such as nausea,vomiting, and the use of antiemetictherapy were higher with ketamineuse.96,97 Opioid administration hasbeen shown to cause N -methyl-D-aspartate (NMDA) activation, whichmay be linked to paradoxical noci-ceptive stimulation and opioid toler-ance. Low-dose ketamine appears toinhibit activation of NMDA recep-tors, leading to decreased opioid tol-erance and consumption.98,99 Patientsexhibiting tolerance with escalatingdoses of opioids or hyperalgesia afteropioid administration may have im-proved pain control and a decrease

Table 3.

Properties of Selected Nonopioid Analgesics30,74,92-94,a

Medication or Class Mechanism of Action Route(s) ofAdministration Clinical Advantages

aNMDA = N -methyl-D-aspartate.

Acetaminophen

Nonsteroidal

antiinflammatory drugs

Local anesthetics

Ketamine

Anticonvulsants

Reduction of prostaglandin

synthesis

Reduction of prostaglandin

synthesis

Blockade of sodium channels

Inhibition of NMDA receptors

Blockade of N -type calcium

and sodium channels

Enteral, i.v., rectal

Enteral, i.m., i.v.

Regional and local

infiltration

Enteral, i.v.

Enteral

Decreases opioid consumption;

provides mild analgesia

Decrease opioid consumption; provide

mild analgesia

Decrease need for opioids for regional

pain; decrease opioid consumption

Decreases opioid tolerance and opioid-

related adverse events

May be effective for neuropathic pain

in opioid-related adverse events withthe use of ketamine.

NSAIDs. NSAIDs inhibit cycloox- ygenase, the catalyst responsible forconverting arachidonic acid to pros-

taglandins and, thereby, reducingprostaglandin-mediated inflamma-tion. This action is particularly usefulin acute pain with an inflammatorycomponent, as seen in surgical pa-tients and patients undergoing otherinvasive procedures. NSAIDs arehighly effective in mild-to-moderatepain and are devoid of many adverseeffects commonly seen with opioids.The use of NSAIDs prior to nocicep-tion and the release of inflammatory

mediators may reduce the pain re-sponse and decrease the likelihood oflong-term sequelae such as chronicpain.100 In postoperative patients,the use of diclofenac, indomethacin,or ibuprofen was associated with adecrease in pain scores as well as con-comitant opioid use.101-103 There wereno differences in rates of renal dys-function or bleeding, common ad-verse effects associated with NSAIDs,in any of the three trials. Althoughthere were no differences in adverseeffects in these trials, NSAIDs shouldbe used with caution in certain pa-tient populations, such as coronaryartery bypass graft (CABG) surgerypatients, due to increased cardiovas-cular and bleeding risks.

Diclofenac was shown to decreasethe time to extubation as well as theneed for rescue analgesic doses andinotropic therapy in a study of pa-tients undergoing CABG surgery.104

Patients were randomly assigned toreceive a continuous i.v. infusion ofpropofol and fentanyl or remifentanilperioperatively and, once transferredto the postcardiac surgery unit, werecontinued on continuous or inter-mittent fentanyl i.v. or diclofenacsuppositories in addition to propofoland rescue doses of fentanyl or intra-muscular diclofenac. There were nodifferences in intraoperative admin-istration of anesthesia between the

three groups, but patients in the di-clofenac group required significantlyless postoperative analgesics andpropofol than those in the compara-tor groups; the patients receiving di-clofenac suppositories also requiredsignificantly less inotropic support,possibly due to the hemodynamiceffects of remifentanil and fentanyl.This study highlighted the potentialopioid-sparing effects of NSAIDsand called into question the overallneed for routine opioid use in selectpatient populations.

Local anesthetics. Local anesthet-ics continue to be the backbone of in-traoperative analgesia; however, theirrole in medical and surgical criticallyill patients continues to evolve.105 The


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most commonly used agents in theinpatient setting include the amideslidocaine, bupivacaine, ropivacaine,and mepivacaine. Local anestheticsexert their nerve conduction–blocking

analgesic mechanism by blocking theentry of sodium ions in Aδ and Cnerve fibers involved in pain trans-mission.106 Motor block is mediatedby inhibition of conduction on Aβ fibers. Local anesthetics can be usedpreemptively and as part of a patient’sbasal pain regimen. Advancementsin technology related to location ofnerves, catheter placement for infu-sions, and medication delivery haveallowed for safer and more directed

administration of local anesthetics inthe inpatient setting.107,108

The American Society of Anesthe-siologists perioperative pain guide-lines recommend an individualizedmultimodal pain management planusing techniques such as centralregional and peripheral regionalanalgesia, including but not limitedto intercostal blocks, plexus blocks,and local anesthetic infiltration ofincisions according to provider andinstitutional capacity to provide safeanalgesic therapy.109 The guidelinesprovide no specific recommenda-tions for perioperative managementof critically ill patients. The currentSCCM–American College of CriticalCare Medicine (ACCM) guidelineson management of pain, agitation,and delirium in adult ICU patientsrecommend that neuraxial anes-thesia and analgesia techniques beconsidered for patients undergoingabdominal aortic aneurysm surgery

and traumatic rib fractures.30 Dueto a lack of ICU-specific data, theSCCM–ACCM guidelines do notprovide recommendations for theuse of local anesthetics in the medi-cal ICU setting; however, these agentsare routinely provided to critically illpatients using a variety of adminis-tration techniques.110

Local anesthetics are routinelyemployed preemptively using asubcutaneous single-injection tech-

nique for procedures in the ICUsuch as arterial or central venouscatheter placement, drain and chesttube placement, and bedside surgi-cal procedures.110 Administration of

local anesthetics using a variety ofregional and local wound infiltrationtechniques in critically ill patientpopulations has been reported in avariety of contexts (e.g., rib fractures,major abdominal surgery, thoracicsurgery, cardiac surgery, orthopedicsurgery, pancreatitis, cancer pain).111 Perioperative studies have shownthat when used as part of a multi-modal regimen, local anesthetics canreduce acute postoperative pain, opi-

oid consumption, opioid-related ad-verse drug effects, pulmonary com-plications, rehabilitation time, lengthof stay, and, potentially, mortality inselect surgical populations.107,111-113

Local anesthetics are a staple inthe surgical realm; however, some pa-tient populations cannot receive localanesthetics due to contraindicationrelated to the drug or the adminis-tration technique.114 For patients re-ceiving antithrombotic therapy andneuraxial administration of local an-esthetics, certain medications may becontraindicated or require specialistmonitoring in order to ensure safeadministration in the ICU.115

Peripheral nerve catheter infu-sions of local anesthetics removethe risk of spinal hematoma but stillrequire specialist consultation andfollow-up.110 Local wound infiltra-tion, or local infiltration analgesia(LIA), is another administrationtechnique that involves the injection

and/or infusion of local anestheticnear the site of surgical incision toprovide targeted analgesia that doesnot require specialist consultationand follow-up.107 A wide variety ofLIA techniques have been described,including single-injection intraop-erative wound infiltration, the use ofindwelling wound infusion catheters,and a recently developed high-volumeLIA technique used in joint replace-ment surgery.3 Wound infusions of

local anesthetics have been demon-strated to reduce pain and opioidconsumption in cardiac and thoracicsurgery populations.107,114,116-118

Local anesthetics are not with-

out risk and, depending on theadministration technique, can posethe potential for local or systemicadverse effects. Potential adverse ef-fects include cardiovascular toxicity(i.e., arrhythmias, hypotension, andreduced myocardial conductivity andcontractility), central nervous systemtoxicity (i.e., seizures), infection,urinary retention, spinal hematoma,and nerve injury.119

Other agents. The pharmacologic

management of neuropathic pain iscategorized according to the suspect-ed location (peripheral or central) ofnerve injury or dysfunction. Periph-eral neuropathic pain managementis focused on decreasing nociceptorsensitization with the use of agentsthat alter the movement of sodium,potassium, and calcium across nervemembranes; these agents includecarbamazepine, oxcarbazepine, la-motrigine, topiramate, and topicallidocaine. Central neuropathic painmanagement aims to inhibit cen-tral hypersensitization with GABAagonists such as gabapentin andalter the modulation of descendinginhibition with drugs such as tri-cyclic antidepressants and selectiveserotonin reuptake inhibitors.120 The available data for treatment ofneuropathic pain are largely cen-tered in chronic pain management,and there are limited data availableregarding the acute treatment of

the critically ill. Two studies showeda significant reduction in fentanyluse for the treatment of pain inGuillain-Barré syndrome with theaddition of gabapentin or carbam-azepine, but data in other patientpopulations are lacking.121,122

Analgosedat ion. The idea of apain-first approach extends beyondpain itself and can be employed inthe realm of sedation as well. Anal-gosedation, the use of an analgesic


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for both pain and sedation, hasbeen shown to decrease exposureto sedative–hypnotic medications,the duration of mechanical ventila-tion, and ICU and hospital length of

stay, with a trend toward decreasedICU mortality.123,124 Analgosedationis generally performed with opioidsthat can be given as a bolus or aneasily titratable continuous infusionand is associated with lower risks ofaccumulation and adverse effects thanare seen with conventional opioid andsedative regimens.123,125-128 Patientsshould be assessed for pain and moni-tored for opioid withdrawal on wean-ing and discontinuation of continu-

ous infusions, particularly patientswith prolonged exposure.129 The useof enteral agents such as methadonehas been shown to decrease mechani-cal ventilation wean time in patientsreceiving continuous infusions offentanyl and should be considered inpatients with baseline pain and thoseat risk for opioid withdrawal.130

Consideration of adverse effects.There are many adverse effects as-sociated with the use of analgesics incritically ill patients. The prolongeduse of opioid continuous infusionsmay be associated with immunosup-pression and subsequent ICU-relatedinfection, and respiratory depres-sion is considered the most severeadverse effect associated with theuse of opioid analgesics, althoughthe effect may be useful for ventila-tor compliance in certain patientpopulations.131,132 Pain medicationuse in end-of-life and palliative caresituations needs to be judiciously as-

sessed and monitored to ensure thatappropriate pain management is be-ing provided despite adverse effectsthat may in fact hasten death.133,134 Organ dysfunction and an increasedrisk of bleeding are possible adverseeffects associated with commonlyused agents for multimodal therapysuch as acetaminophen and NSAIDs.Critically ill patients should be close-ly monitored for changes in organfunction and disease status, which

may necessitate switching or discon-tinuing certain analgesic agents.

Conclusion

Acute pain management in the

critically ill is a largely underassessedand undertreated area of criticalcare. Opioids are the cornerstoneof treatment, though a multimodalapproach may improve patient out-comes and decrease opioid-relatedadverse events.

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