1. © 2009 BC Decker Inc ACS Surgery: Principles and Practice
1 BASIC SURGICAL AND PERIOPERATIVE CONSIDERATIONS 6 POSTOPERATIVE PAIN — 1
6 POSTOPERATIVE PAIN
Spencer S. Liu, MD, and Henrik Kehlet, MD, PHD, FACS (Hon)
Clinical Approach to the Patient with Postoperative Pain
Postoperative pain con- Guidelines for Postoperative Pain Treatment
sists of a constellation of In the past few years, efforts have been made to develop
unpleasant sensory, emo- procedure-specific perioperative pain management guide-
tional, and mental experi- lines. The impetus for these efforts has been the realization
ences associated with that the analgesic efficacy may be procedure dependent
autonomic, psychological, and that the choice of analgesia in a given case must also
and behavioral responses precipitated by the surgical injury. depend on the benefit-to-risk ratio, which varies among
Pain management has received increasing attention, and mul- procedures. In addition, it is clear that some analgesic
tiple government agencies and medical specialty organiza- techniques will be considered only for certain specific
tions have now created guidelines for treatment of operations (e.g., peripheral nerve blocks and intraperito-
postoperative pain.1 In 2001, the Joint Commission on neal local anesthesia).6–8 At present, these procedure-
Accreditation of Healthcare Organizations (JCAHO) intro- specific guidelines are still largely in a developmental state
duced standards for pain management,2 stating that patients and are available for laparoscopic cholecystectomy, open
have the right to appropriate evaluation and management and colon surgery, hysterectomy, inguinal hernia repair, thora-
that pain must be assessed. cotomy, mastectomy, hemorrhoidectomy, and knee and
Postoperative pain relief has two practical aims. The first hip replacement.9,10
is provision of subjective comfort, which is desirable for
humanitarian reasons. The second is inhibition of trauma- thoracic
induced nociceptive impulses to blunt autonomic and procedures
somatic reflex responses to pain and to enhance subsequent Pain after thoracotomy
restoration of function by allowing the patient to breathe, is severe, and pain therapy
cough, and move more easily. Because these effects reduce should therefore include a
pulmonary, cardiovascular, thromboembolic, and other combination regimen,
complications, they may lead secondarily to improved post- preferably comprising epidural local anesthetics and opi-
operative outcome. oids11 combined with systemic nonsteroidal antiinflammatory
drugs (NSAIDs) or cyclooxygenase-2 (COX-2) inhibitors
Inadequate Treatment of Pain (depending on risk factors) [see algorithm]. If the epidural
regimen is not available, then comparable analgesia may be
A common misconception is that pain, no matter how
achieved with continuous thoracic paravertebral block, with
severe, can always be effectively relieved by opioid analgesics.
It has repeatedly been demonstrated, however, that in a high
proportion of postoperative patients, pain is inadequately Table 1 Contributing Causes of Inadequate Pain
treated.3,4 This discrepancy between what is possible and Treatment
what is practiced can be attributed to a variety of causes [see Insufficient knowledge of drug pharmacology among surgeons and
Table 1], which to some extent can be ameliorated by increased nurses
teaching efforts. Recent evidence also indicates that overreli- Uniform (p.r.n.) prescriptions
ance on opioid therapy may be inherently limiting because of
development of both acute tolerance and opioid-induced Lack of concern for optimal pain relief
hyperalgesia.5 The ability of opioids in high doses or with Failure to give prescribed analgesics
chronic administration to potentially induce pain illustrates Fear of side effects
the importance of using multimodal analgesic regimens that
Fear of addiction
target multiple analgesic pathways.
DOI 10.2310/7800.S01C06
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1 BASIC SURGICAL AND PERIOPERATIVE CONSIDERATIONS 6 POSTOPERATIVE PAIN — 2
Combine complementary alternative medicine with pharmalogic
and other interventions to treat postoperative pain
• Consider recommended multimodal combination regimens.
• Acetaminophen is recommended as a basic component of
multimodal analgesia in any of the settings listed below.
Thoracic Abdominal
Cardiac Noncardiac Major Open
Give systemic opioids Give epidural analgesia or Give epidural analgesia
with NSAIDs or COX-2 continuous paravertebral with NSAIDs or COX-2
inhibitors. block with NSAIDs or inhibitors.
Consider epidural COX-2 inhibitors. Secondary Choice:
analgesia or parasternal Secondary Choice: Give systemic PCA
wound catheter with local Give systemic PCA opioids with NSAIDs or
anesthetic. opioids with NSAIDs or COX-2 inhibitors.
COX-2 inhibitors.
COX-2 = cyclooxygenase-2, NSAIDs = nonsteroidal antiinflammatory drugs; PCA = patient-controlled analgesia.
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3. © 2009 BC Decker Inc ACS Surgery: Principles and Practice
1 BASIC SURGICAL AND PERIOPERATIVE CONSIDERATIONS 6 POSTOPERATIVE PAIN — 3
Clinical Approach to the Patient
with Postoperative Pain
Pelvic Peripheral
Prostatectomy Gynecologic Vascular Major Joint Procedures
Give epidural analgesia Give systemic PCA Give epidural local Give continuous or single-
or systemic PCA opioids opioids with NSAIDs or anesthetics with NSAIDs dose perineural analgesia
with NSAIDs or COX-2 COX-2 inhibitors. or COX-2 inhibitors. (femoral or lumbar plexus)
inhibitors. Secondary Choice: Secondary Choice: with NSAIDs or COX-2
Give epidural analgesia. Give systemic opioids inhibitors.
with NSAIDs or COX-2 Secondary Choice:
inhibitors. Give systemic PCA or
single-dose spinal opioids
with NSAIDs or COX-2
inhibitors. Consider single-
dose perineural analgesia.
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4. © 2009 BC Decker Inc ACS Surgery: Principles and Practice
1 BASIC SURGICAL AND PERIOPERATIVE CONSIDERATIONS 6 POSTOPERATIVE PAIN — 4
the potential for lesser incidence of urinary retention and Pain relief after major joint procedures (e.g., hip and knee
postoperative nausea and vomiting.12 Although comparable, operations)10 may involve an epidural regimen in certain high-
the continuous paravertebral technique may be more techni- risk patients because such regimens have been shown to reduce
cally difficult. If neither regional analgesic technique is thromboembolic complications and intraoperative blood loss
available, then the inferior regimen of NSAIDs and systemic and to improve physical rehabilitation when compared with
opioids may be used. Cryoanalgesia is not recommended as systemic opioid regimens.17,18 However, the severe pain noted
it is less effective.10 Acetaminophen is recommended as a after knee replacement is probably best treated with peripheral
basic analgesic for multimodal analgesia. Pain after cardiac nerve blocks.10,19 Most of the benefit of continuous femoral
operation with sternotomy is less severe, and systemic opi- nerve analgesia may also be achieved with a single-injection
oids plus NSAIDs are recommended. The combined regi- femoral nerve block.20 Total hip replacement is a less painful
men of epidural local anesthetics and opioids or parasternal procedure, but when pain is severe, a continuous lumbar
wound catheters with continuous administration of local plexus or femoral nerve block can be used.10,21 Alternatively
anesthetics13 is recommended when more effective pain and with less technical expertise, a single intrathecal dose of
relief is necessary, and it may reduce cardiopulmonary mor- local anesthetic and low-dose morphine will provide effective
bidity and perhaps length of stay.14 analgesia for the first 8 to 16 hours,10 after which NSAIDs or
COX-2 inhibitors may be added. Acetaminophen is provided
abdominal as a basic analgesic for multimodal analgesia.
procedures
Pain after major and Treatment Modalities
upper open abdominal
operations is severe, and a complementary and alternative medicine
combined regimen of epi- interventions
dural local anesthetics and opioids is recommended because Cognitive, behavioral, alternative, or social interventions
it has proved to be superior to systemic opioids and to have should be used in combination with pharmacologic therapies to
few and acceptable side effects.10,11,15 Furthermore, the epidu- prevent or control acute pain, with the goal of such interven-
ral regimen will reduce postoperative pulmonary complica- tions being to guide the patient toward partial or complete self-
tions and ileus compared with treatment with systemic control of pain.22,23 A recent survey by the American Hospital
opioids.16 Systemic NSAIDs or COX-2 inhibitors are added Association indicated that 27% of member hospitals offered
when needed. Acetaminophen is recommended as a basic complementary and alternative medications (CAMs).24 Use of
analgesic for multimodal analgesia. nonpharmacologic adjunctive analgesics has been endorsed by
After gynecologic lower abdominal or pelvic operations,10 advisory bodies such as the Anesthesia Patient Safety Founda-
systemic opioids plus NSAIDs or COX-2 inhibitors are rec- tion and Institute of Healthcare Improvement.25,26
ommended except in patients in whom more effective pain Psychological preparation in patients with postoperative pain
relief is desirable. In such patients, the combined regimen of has been demonstrated to shorten hospital stay and reduce
epidural local anesthetics and opioids is preferable. Acet- postoperative narcotic use [see Table 2].27 Guided imagery,
aminophen is recommended as a basic analgesic for multi- relaxation, and music techniques have been demonstrated to
modal analgesia. reduce postoperative opioid use and affective pain.22 Acupunc-
Pain following prostatectomy is usually not severe and may ture and acupressure has been successfully used as an adjunct
be treated with systemic opioids combined with NSAIDs or for postoperative analgesia and reduces pain scores, anxiety
COX-2 inhibitors and acetaminophen. However, blood loss levels, and postoperative nausea.28 Alternative techniques
and thromboembolic complications are reduced when epidu-
ral local anesthetics are administered. This method is there-
fore recommended intraoperatively and continued in selected Table 2 Psychological Preparation of Surgical Patients
high-risk patients for pain relief after open prostatectomy and Procedural information
transurethral resection. In low-risk patients, systemic opioids Give a careful and relevant description of what will take place.
with NSAIDs or COX-2 inhibitors and acetaminophen allevi-
Sensory information
ate postoperative pain. Describe the sensations that will be experienced either during or
after the operation.
peripheral Pain treatment information
procedures Outline the plan for administering sedative and analgesic medi-
cation and encourage patients to communicate concerns and
After vascular proce- discomforts.
dures, postoperative pain
Instructional information
control is probably best
Teach patients postoperative exercises, such as leg exercises,
achieved with epidural and show them how to turn in bed or move so that pain is
local anesthetic–opioid mixtures, combined with systemic minimal.
NSAIDs or COX-2 inhibitors.11 Acetaminophen is recom- Reassurance
mended as a basic analgesic for multimodal analgesia. This Reassure those who are mentally, emotionally, or physically
regimen will be effective, and the increase in peripheral blood unable to cooperate that they are not expected to take an active
flow that is documented to occur with epidural local anes- role in coping with pain and will still receive sufficient analgesic
treatment.
thetics may lower the risk of graft thrombosis.
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Table 3 Opioid Receptor Types and Physiologic Actions
Prototypical Ligand
Receptor Type Endogenous Exogenous Physiologic Actions
1
Mu ß-Endorphin Morphine Supraspinal analgesia
2
Mu ß-Endorphin Morphine Respiratory depression
Delta Enkephalin — Spinal analgesia
Kappa Dynorphin Ketocyclazocine Spinal analgesia, sedation, visceral analgesia
should be combined with pharmacologic or other interven- administration of an agonist-antagonist with a complete agonist
tions, but care must be taken to ensure that the pharmacologic may cause a reduction in the effect of the complete agonist.29
treatment does not compromise the mental function necessary
for the success of the planned psychological intervention. Agents
Morphine Morphine is the opioid with which the most
systemic opioids clinical experience has been gained. Sufficient pharmacoki-
Mechanisms of Action netic and pharmacodynamic data are available. Use of this
Opioids produce analgesia and other physiologic effects by agent is recommended; it may be given orally, intravenously
binding to specific receptors in the peripheral and central ner- (IV), or intramuscularly (IM).
vous system (CNS) [see Table 3]. These receptors normally Meperidine Detailed and sufficient pharmacokinetic
bind a number of endogenous substances called opioid pep- and pharmacodynamic data on meperidine are available. It is
tides. These receptor-binding interactions mediate a wide array less suitable than morphine as an analgesic because its active
of physiologic effects.29 Three types of opioid receptors and
their subtypes have been discovered: mu, delta, and kappa Table 4 Intrinsic Activity of Opioids
receptors. The most commonly used opioids bind to mu recep-
tors. The mu1 receptor is responsible for the production of Opioid Mu Kappa Delta
opioid-induced analgesia, whereas the mu2 receptor appears to Agonists
be related to the respiratory depression, cardiovascular effects, Morphine Agonist —
and inhibition of GI motility commonly seen with opioids.
Meperidine Agonist —
The discovery of peripheral opioid receptors has led to (Demerol)
investigation into potential clinical applications. Phase III
studies with alvimopan (a peripheral opioid antagonist that Hydromorphone Agonist
(Dilaudid)
does not cross the blood-brain barrier) have demonstrated
reduced ileus and hospitalization after abdominal surgery.30 Oxymorphone Agonist
(Numorphan)
Other studies have also investigated the analgesic effects of
applying opioids to wound sites in an attempt to provide Levorphanol Agonist
peripheral analgesia without central side effects. Unfortunately, (Levo-
Dromoran)
neither incisional31 nor intra-articular32 opioid administration
has demonstrated significant beneficial effect.30 This finding Fentanyl Agonist
may be attributable to the need for chronic inflammatory medi- (Duragesic)
ators to facilitate expression of peripheral opioid receptors.33 Sufentanil Agonist
The relation between receptor binding and the intensity of (Sufenta)
the resultant physiologic effect is known as the intrinsic activ- Alfentanil (Alfenta) Agonist
ity of an opioid. Most of the commonly used opioid analge- Methadone Agonist
sics are agonists. An agonist produces a maximal biologic (Dolophine)
response by binding to its receptor. Other opioids, such as
Agonist-Antagonists
naloxone, are termed antagonists because they compete with
agonists for opioid receptor-binding sites. Still other opioids Buprenorphine Partial
(Buprenex) agonist
are partial agonists because they produce a submaximal
response after binding to the receptor. (An excellent example Burtorphanol Antagonist Agonist Agonist
of a submaximal response produced by partial agonists is (Stadol)
buprenorphine’s action at the mu receptor.) Nalbuphine Antagonist Partial Agonist
Drugs such as nalbuphine, butorphanol, and pentazocine are (Nubain) agonist
known as agonist-antagonists or mixed agonist-antagonists.29 Pentazocine Antagonist Agonist Agonist
These opioids simultaneously act at different receptor sites: their (Talwin)
action is agonistic at one receptor and antagonistic at another Dezocine (Dalgan) Partial
[see Table 4]. The agonist-antagonists have certain pharmaco- agonist
logic properties that are distinct from those of the more common Antagonists
mu agonists: (1) they exhibit a ceiling effect and cause only
submaximal analgesia compared with mu agonists and (2) Naloxone (Narcan) Antagonist Antagonist Antagonist
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metabolite, normeperidine, can accumulate, even in patients about 30% of the time during any 4-hour dosing interval.
with normal renal clearance, and this accumulation can result The optimal means to treat moderate to severe postoperative
in CNS excitation and seizures.29 Other agents should be pain with systemic opioids is via IV patient-controlled anal-
used before meperidine is considered. Like morphine, meper- gesia (PCA). This delivery system compensates for the wide
idine can be given orally, IV, or IM. inter- and intraindividual variability in analgesic needs and
blood levels after opioid administration. Self-delivery helps
Side Effects produce timely titration of analgesia and reduces administra-
By depressing or stimulating the CNS, opioids cause a tive delay from conventional delivery (e.g., p.r.n.). Systematic
number of physiologic effects in addition to analgesia. The reviews have noted that IV PCA delivery of opioids reduces
depressant effects of opioids include analgesia, sedation, and pain scores and improves patient satisfaction over conven-
altered respiration and mood; the excitatory effects include tional delivery.34 Typical regimens are provided in Table 5.
nausea, vomiting, and miosis. Recent advances in iontophoretic technology have led to
All mu agonists produce a dose-dependent decrease in the commercial release of a transdermal fentanyl iontophoretic
responsiveness of brainstem respiratory centers to increased PCA system. This system delivers 40 µ g fentanyl over
carbon dioxide tension (Pco2). This change is clinically man- 10 minutes after patient demand. Onset is rapid because of
ifested as an increase in resting Pco2 and a shift in the CO2 the active electrical current driving the fentanyl transder-
response curve. Agonist-antagonist opioids have a limited mally. The system deactivates after 24 hours or 80 adminis-
effect on the brainstem and appear to elicit a ceiling effect on trations. Several clinical trials have reported equivalence
increases in Pco2. between the fentanyl system and IV PCA opioid.35 One
Opioids also have effects on the gastrointestinal (GI) tract. pooled analysis suggested less analgesic gaps with the fentanyl
Nausea and vomiting are caused by stimulation of the che- system because of fewer technical failures and administrative
moreceptor trigger zone of the medulla. Opioids enhance delays than the IV PCA device36; however, the role of this
sphincteric tone and reduce peristaltic contraction. Delayed fentanyl system remains to be fully defined.
gastric emptying is caused by decreased motility, increased
antral tone, and increased tone in the first part of the duode- epidural and subarachnoid opioids
num. Delay in passage of intestinal contents because of
Opioids were first used in the epidural and subarachnoid
decreased peristalsis and increased sphincteric tone leads to
spaces in 1979. Since that time, they have become the main-
greater absorption of water, increased viscosity, and desicca-
stay of postoperative management for severe pain. Epidural
tion of bowel contents, which cause constipation and contrib-
opioids may be administered in a single bolus or via continu-
ute to postoperative ileus. Opioids also increase biliary tract
ous infusions. They are usually combined with local anesthet-
pressure. Finally, opioids may inhibit urinary bladder func-
ics in a continuous epidural infusion to enhance analgesia.37
tion, thereby increasing the risk of urinary retention.
Several long-acting, slow-release oral opioids are currently
available, but their role (in particular, their safety) in the set- Mechanisms of Action
ting of moderate to severe postoperative pain remains to be Opioids injected into the epidural or subarachnoid space
established. In addition, modern principles of treatment cause segmental (i.e., selective, spinally mediated) analgesia
increasingly emphasize the use of opioid-sparing analgesic by binding to opioid receptors in the dorsal horn of the spinal
approaches to enhance recovery (see below). cord.38 The lipid solubility of an opioid, described by its par-
tition coefficient, predicts its behavior when introduced into
clinical application of systemic opioids the epidural or subarachnoid space. Opioids with low lipid
Traditional IM dosing of opioids is a suboptimal means of solubility (i.e., hydrophilic opioids) have a slow onset of
analgesia.34 IM dosing does not result in consistent blood action and a long duration of action. Opioids with high lipid
levels, because opioids are absorbed at a variable rate from solubility (i.e., lipophilic opioids) have a quick onset of action
the vascular bed of muscle. Moreover, administration of tra- but a short duration of action. This is attributable to more
ditional IM regimens results in opioid concentrations that rapid diffusion across the dura into the spinal cord but
exceed the concentrations required to produce analgesia only also more rapid systemic uptake and clearance via uptake into
Table 5 Typical Intravenous Patient-Controlled Analgesia Regimens
Drug Concentration Size of Bolus Lockout Interval (min)
Agonists
Morphine (1 mg/mL)
Adult 0.5–2.5 mg 5–10
Pediatric 0.01–0.03 mg/kg (max. = 0.15 mg/kg/hr) 5–10
Fentanyl (0.01 mg/mL)
Adult 10-20 ug 4–10
Pediatric 0.5–1 µ g/kg (max. = 4 µ g/kg/hr) 5–10
Hydromorphone (0.2 mg/mL)
Adult 0.05–0.25 mg 5–10
Pediatric 0.003–0.005 mg/kg (max. = 0.02 mg/kg/hr) 5–10
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epidural and spinal cord blood vessels. In fact, current Naloxone reverses the depressive respiratory effects of spinal
evidence suggests that a major site of action of spinal lipo- opioids. In an apneic patient, 0.4 mg IV will usually restore
philic opioids is not the spinal cord but the brain via systemic ventilation. If a patient has a depressed respiratory rate but is
uptake.39 Thus, lipophilic opioids as sole epidural analgesic still breathing, small aliquots of naloxone (0.2 to 0.4 mg) can
agents are becoming less frequently recommended. be given until the respiratory rate returns to normal.
Subarachnoid opioids should be used when the required Nausea and vomiting are caused by transport of opioids to
duration of analgesia after surgery is relatively short (< 24 hours) the vomiting center and the chemoreceptor trigger zone in
because of typical single-injection delivery. When protracted the medulla via CSF flow or the systemic circulation. Nausea
analgesia is required, epidural administration is preferred; can usually be treated with antiemetics or, if severe, with nal-
repeated injections may be given through epidural catheters, or oxone (in 0.2 mg increments, repeated if necessary).
continuous infusions may be used. Smaller doses of subarach- Pruritus is probably the most common side effect of the
noid opioids are generally required to produce analgesia. Ordi- spinal opioids. Although not fully defined, the mechanism
narily, no more than 0.1 to 0.25 mg of morphine should be used likely involves activation of “itch-specific” opioid receptors
to provide 12 to 24 hours of analgesia. These doses, which are on spinal sensory neurons.45 Although pruritus is commonly
about 10 to 20% of the size of comparably effective epidural treated with antihistamines, there is minimal evidence for
doses, provide reliable pain relief with few side effects.40 Fen- mechanism-specific effectiveness. An alternative and proba-
tanyl has also been extensively used in the subarachnoid space bly superior treatment is use of a mixed opioid agonist antag-
in a dose range of 6.25 to 25 µ g to provide 3 to 6 hours of onist to directly block the opioid receptor–induced itching
analgesia. Recently, an extended duration formulation of epidu- while maintaing opioid analgesias. Doses of 5 mg of nalbu-
ral morphine has been commercially released.41–43 phine IV or 2 to 4 mg of butorphanol intranasally or IV every
This formulation consists of morphine encased in multive- 6 hours is commonly used.45
sicular lipid with predictable sustained release. Clinical stud- The mechanism of spinal opioid–induced urinary retention
ies have overall supported the efficacy and general safety of involves inhibition of volume-induced bladder contractions
this formulation (10–15 mg doses) without demonstrating and blockade of the vesical reflex. Naloxone administration is
marked superiority over conventional central neuraxial opioid the treatment of choice, although bladder catheterization is
therapy. Thus, the role of this preparation remains to be sometimes required.
determined.
clinical application of epidural and
Side Effects subarachnoid opioids
The chief side effects associated with epidural and As stated earlier, subarachnoid opioids are limited in the
subarachnoid opioids are respiratory depression, nausea and duration of analgesia because of typical single-injection deliv-
vomiting, pruritus, and urinary retention.38,40,44 The poor lipid ery. Epidural administration allows prolonged delivery of opi-
solubility of morphine is responsible for its protracted dura- oids, and typical regimens are listed in Table 6. However,
tion of action but also allows morphine to undergo cephalad side effects from opioids are common, and it is better to com-
migration in the cerebrospinal fluid (CSF). This migration bine epidural opioids with local anesthetics to obtain multi-
can cause delayed respiratory depression, with a peak inci- modal and synergistic analgesia. This allows smaller doses of
dence 3 to 10 hours after an injection. The high lipid solubil- both agents to be used with better analgesia and fewer side
ity of lipophilic opioids such as fentanyl allows them to be effects. Typical regimens are listed in Table 7.
absorbed into lipids close to the site of administration. Con-
sequently, the lipophilic opioids do not migrate rostrally in epidural local anesthetics and other
the CSF and cannot cause delayed respiratory depression. Of regional blocks
course, the high lipid solubility of lipophilic opioids allows Local anesthetic neural blockade is unique among available
them to be absorbed into blood vessels, which may cause analgesic techniques in that it may offer sufficient afferent
early respiratory depression, as is commonly seen with sys- neural blockade, resulting in relief of pain; avoidance of seda-
temic administration of opioids. Overall, the typical incidence tion, respiratory depression, and nausea; and, finally, efferent
of respiratory depression is similar to that seen with systemic sympathetic blockade, resulting in increased blood flow to the
opioids at approximately 0.2%.44 region of neural blockade.46
Table 6 Typical Dosing of Neuraxial Opoids
Intrathecal or Subarachnoid
Drug Single Dose Epidural Single Dose Epidural Continuous Infusion
Fentanyl 5–25 µ g 50–100 µ g 25–100 µ g/hr
Sufentanil 2–10 µ g 10–50 µ g 10–20 µ g/hr
Morphine 0.1–0.3 mg 1–5 mg 0.1–1 mg/hr
Hydromorphone — 0.5–1 mg 0.1–0.2 mg/hr
Meperidine 10–30 mg 20–60 mg 10–60 mg/hr
Lower doses may be effective when administered to the elderly or when injected in the cervical or thoracic region. Units vary across agents for single dose (mg
versus µ g) and continuous infusion (mg/hr versus µ g/hr).
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Table 7 Typical Patient-Controlled Epidural Analgesia Regimens
Analgesic Solution Continuous Rate (mL/hr) Demand Dose (mL) Lockout Interval (min)
0.0625–0.125% bupivacaine + 2–5 µ g/mL 4–6 3–4 10–15
fentanyl
0.125–0.125% bupivacaine + 2–5 µ g//mL 3–5 2–3 12
sufentanil
0.1–0.2% ropivacaine + 2–4 µ g//mL 3–5 2–5 10–20
fentanyl
Mechanism of Action clinical application of continuous epidural
Local anesthetic neural blockade is a nondepolarizing block analgesia
that reduces the permeability of cell membranes to sodium Typical regimens are listed in Table 7. As is similar with
ions.47 Whether different local anesthetics have different IV PCA, patient-controlled epidural analgesia (PCEA) has
effects on different nerve fibers is debatable. been demonstrated to provide superior analgesia, decreased
analgesic consumption, and decreased side effects.51 The
Choice of Drug safety of PCEA regimens for hospital wards has been well
For optimal management of postoperative pain, the anes- documented.52 As all epidural analgesic agents are deliber-
thetic agent should provide excellent analgesia of rapid onset ately segmental (limited in anatomic spread) in nature, it is
and long duration without inducing motor blockade. The important for the vertebral site of epidural placement to
various local anesthetic agents all meet one or more of these match the site of surgery. For example, lumbar epidurals
criteria; however, the ones that come closest to meeting all of offer inferior analgesia to thoracic epidurals for thoracic sur-
the criteria are bupivacaine, ropivacaine, and levobupivacaine. gery. Suggested epidural sites are also listed in Table 9.
This should not preclude the use of other agents, because
their efficacy has also been demonstrated. Ropivacaine and other regional analgesia techniques
levobupivacaine may have a better safety profile, but the Intraperitoneal administration of local anesthetics cannot
improvement may be relevant only when high intraoperative be recommended for typical postoperative analgesia,
doses are given.47 because they are not efficacious,53 except in laparoscopic
cholecystectomy.8,10 Intraincisional administration of bupi-
Side Effects
vacaine or other long-acting local anesthetics, which has
The main side effects of epidural local anesthesia are hypo- negligible side effects and demands little or no surveillance,
tension caused by sympathetic blockade, vagal overactivity, is recommended for patients undergoing relatively minor
and decreased cardiac function (during a high thoracic block). procedures.
Under no circumstances should epidural local anesthetics be Continuous administration of local anesthetics into the
used before a preexisting hypovolemic condition is treated. wound via a catheter directly placed at the end of surgery is
Hypotension may be treated with ephedrine, 10 to 15 mg IV, a simple and efficacious means to provide postoperative
and fluids, with the patient tilted in a head-down position. analgesia. A recent systematic review noted that wound
Atropine, 0.5 to 1.0 mg IV, may be effective during vagal catheters improved postoperative analgesia, reduced opioid
overactivity.
Urinary retention occurs in 20 to 100% of patients, and
urinary catheterization is typically used during epidural anal-
Table 8 Procedures for Maintenance of Epidural
gesia. Motor blockade may delay mobilization; however, its Anesthesia for Longer than 24 Hours
incidence can be reduced by using the weakest concentration
1. Administer appropriate drug in appropriate dosage at selected
of local anesthetic that is compatible with adequate sensory
infusion rate as determined by physician
blockade.
The routine complications associated with the epidural 2. Nurse evaluates vital signs and intake and output as required
for a postoperative patient
catheter are minimal when proper nursing protocols are fol-
lowed [see Table 8]. The decision to employ epidural local 3. Nurse checks infusion pump hourly to ensure that it is function-
anesthetics in such patients should be made only after the ing properly, that infusion rate is proper, and that alarm is on
risks44,48 are carefully compared with the documented advan- 4. Nurse also assesses
tages of such anesthetics.49,50 • Bladder—for distention, if patient is not catherized
Spinal hematoma attributable to the combination of epidu- • Lower extremities—for status of motor function
ral analgesia and anticoagulants is rare, but the risk may be • Central nervous system—for signs of toxicity or respiratory
depression
increased by specific agents. Guidelines on the use of epidural • Skin integrity on back (breakdown may occur if motor func-
analgesia and anticoagulation are currently listed on the tion is not present)
American Society of Regional Anesthesia and Pain Medicine • Tubing and dressing (disconnection of tubing or dislodg-
Web site.48 Most anticoagulants can be safely managed with ment of catheter may occur)
epidural analgesia; however, special care must be taken with 5. Every 48 hr, the catheter dressing should be removed, the cath-
thrombolytics, low-molecular-weight heparins, and newer eter entrance site cleaned, and topical antibiotic applied (much
antiplatelet, antithrombin, and anti–factor Xa agents. as in care of a central venous catheter)
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Table 9 Recommended Location of Catheter Insertion for Surgical Procedures
Congruent Epidural Catheter
Location of Incision Examples of Surgical Procedures Placement
Thoracic Lung reduction, radical mastectomy, thoracotomy, thymectomy T4–8
Upper abdominal Cholecystectomy, esophagectomy, gastrectomy, hepatic section, Whipple T6–8
procedure
Middle abdominal Cystoprostatectomy, nephrectomy T7–10
Lower abdominal Abdominal aortic aneurysm repair, colectomy, radical prostatectomy, T8–11
total abdominal hysterectomy
Lower extremity Femoropopliteal bypass, total hip or total knee replacement L1–4
L = lumbar; T = thoracic.
use, and decreased opioid-related side effects in a variety of any agent or agents over the others, and selection therefore
procedures.13 However, there is still a need for more may depend on the convenience of delivery, duration, and
procedure-specific data before general recommendations can cost.66 All of the NSAIDs have potentially serious side effects:
be made as a wide variety of surgical procedures, catheter GI and surgical site hemorrhage, renal failure, impaired bone
locations, and analgesic regimens were included in the sys- healing, and asthma. The endoscopically verified superficial
tematic review. ulcer formation seen within 7 to 10 days after the initiation
Continuous peripheral nerve blocks are growing in popular- of NSAID therapy is not seen with selective COX-2 inhibitor
ity, and the analgesic treatment may be continued after dis- treatment in volunteers. The clinical relevance of these find-
charge.54,55 A systematic review has documented multiple ings for perioperative treatment remains to be established,
benefits from the use of continuous perineural analgesia versus however, given that acute severe GI side effects (bleeding,
systemic opioids, such as reduced pain scores at rest and with perforation) are extremely rare in elective cases.
activity, reduced opioid use, reduced opioid-related side Because prostaglandins are important for regulation of
effects, and increased patient satisfaction.54 Use of outpatient water and mineral homeostasis by the kidneys in the dehy-
perineural analgesia is also growing in popularity, and studies drated patient, perioperative treatment with NSAIDs, which
have observed that this form of analgesia reduces unplanned inhibit prostaglandin synthesis, may lead to postoperative
hospital admission after ambulatory procedures, improves renal failure. So far, specific COX-2 inhibitors have not been
patients quality of life at home, and may facilitate conversion demonstrated to be less nephrotoxic than conventional
of hospital procedures to short-stay procedures (e.g., total NSAIDs.62,67 Although little systematic evaluation has been
knee replacement).56 A growing body of literature surveying done, extensive clinical experience with NSAIDs suggests
the use of thousands of perineural catheters for postoperative that the renal risk is not substantial.68 Nonetheless, conven-
analgesia documents a low incidence of complications and tional NSAIDs and COX-2 inhibitors should be used with
overall safety of this technique.57 More recently, a high-volume caution in patients who have preexisting renal dysfunction.62
infiltration technique with dilute concentrations of local anes- Although conventional NSAIDs prolong bleeding time and
thetics with or without adjuvants seems promising because of inhibit platelet aggregation, there generally does not seem to
its apparent efficacy, simplicity, and safety.58,59
nsaids, cox-2 inhibitors, and acetaminophen Table 10 Typical Dosing for Common NSAIDs, COX-2
Inhibitors, and Acetaminophen
NSAIDs and COX-2 inhibitors are modest analgesics that
have both peripheral and central analgesic mechanisms and Typical Dose for Maximum
Postoperative Recommended
antiinflammatory effects [see Table 10]. Although these agents
Drug Analgesia Dose (mg/day)
are typically less effective as sole analgesic agents than opi-
oids,60 they have an excellent efficacy to safety profile and are Acetaminophen 650–1,000 mg q 6 hr 4,000
generally recommended after all kinds of operations for low- Celecoxib 100–200 mg q 12 hr 400
risk patients.61,62 Several reviews and systematic reviews report Diclofenac 50 mg q 8 hr 150
that NSAIDs and COX-2 inhibitors decrease systemic mor-
Ibuprofen 400 mg q 6 hr 3,200
phine use by approximately 13 to 18 mg over a 24-hour
period.61,62 More importantly, these reviews indicate that Indomethacin 25–50 mg q 8 hr 200
NSAIDs decrease pain scores by approximately 1 cm on a 10 cm Ketorolac 10 mg q 4–6 hr 40
visual analogue scale pain score and reduce opioid-related side
Ketorolac 15–30 mg q 6 hr 120
effects of sedation and nausea by approximately 30%. Conven- (intravenous)
tional NSAIDs inhibit both COX-1 and COX-2. Selective
Meloxicam 7.5–15 mg q day 15
COX-2 inhibitors, which do not inhibit COX-1, have the
potential to achieve analgesic efficacy comparable to that of Naproxen 250 mg q 6–8 hr 1,375
conventional NSAIDs but with fewer minor side effects.63–65 Paracetamol 1,000 mg q 6 hr 4,000
Only a few of the NSAIDs may be given parenterally. The (intravenous)
data now available on the use of NSAIDs for postoperative COX-2 = cyclooxygenase; NSAIDs = nonsteroidal antiinflammatory
pain are insufficient to allow definitive recommendation of drugs.
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be a clinically significant risk of increased bleeding. However, of serotonin and norepinephrine.78 It can be used as an intra-
in some procedures for which strict hemostasis is critical venous analgesic but is less potent than opioids (morphine,
(e.g., tonsillectomy, cosmetic surgery, and eye surgery), these meperidine)79 and is a poor sole agent for control of postop-
drugs have been shown to increase the risk of bleeding com- erative pain.80
plications and should therefore be replaced with COX-2 Several systematic reviews have suggested that some anal-
inhibitors, which do not inhibit platelet aggregation.69 The gesic and perioperative opioid-sparing effects can be achieved
observation that prostaglandins are involved in bone and by adding an N-methyl-d-aspartate (NMDA) receptor
wound healing has given rise to concern about potential side antagonist (e.g., ketamine), gabapentin, or pregabalin [see
effects in surgical patients. Although there is experimental Combination Regimens, below].34,81
evidence that both conventional NSAIDs and COX-2 inhib-
itors can impair bone healing,70 the clinical data available at transcutaneous electrical nerve stimulation
present are insufficient to document increased wound or Transcutaneous electrical nerve stimulation (TENS) is the
bone healing failure with these drugs.71 This is a particularly application of a mild electrical current through the skin sur-
important issue for future study in that many orthopedic sur- face to a specific area, such as a surgical wound, to achieve
geons remain reluctant to use NSAIDs. pain relief; the exact mechanism whereby it achieves this
Currently, there is widespread concern about the increased effect is yet to be explained but may involve spinal gating and
risk of cardiovascular complications associated with long-term activation of opioid receptors. Although several randomized
treatment with selective COX-2 inhibitors. Generally, such controlled trials have reported efficacy after inguinal herni-
side effects have appeared only after 1 to 2 years of treatment otomy,82 thoracotomy,83 and other procedures,84 the specific
and led to the withdrawal of rofecoxib in 2004 and valdecoxib values and the proper uses of the various stimulation frequen-
in 2005 from the US market.72 In the past few years, however, cies, waveforms, and current intensities have not been deter-
two studies of patients undergoing coronary artery bypass mined. In addition, blinding of subjects is difficult with TENS
grafting (CABG) found that the risk of cardiovascular com- studies, and this effect of bias is difficult to assess. Overall,
plications was increased significantly (two- to threefold) in the effect of TENS on acute pain is too imprecise to warrant
this setting and led to the label change for COX-2 inhibitors a recommendation for routine use.85
and NSAIDs indicating that these agents are contraindicated
in CABG patients.72 The larger question is whether these combination regimens
drugs should also be contraindicated for perioperative use, or Because no single pain treatment modality is optimal, com-
at least used with caution, in high-risk cardiovascular patients bination regimens (e.g., balanced analgesia or multimodal
who are undergoing procedures other than CABG. At pres- treatment) offer major advantages over single-modality regi-
ent, the data are insufficient to allow final conclusions; none- mens, whether by maintaining or improving analgesia, by
theless, reviews suggest that the benefits of short-term use of reducing side effects, or by doing both.86 Combinations of
these agents in patients without cardiovascular risk factors epidural local anesthetics and morphine,15,44 of NSAIDs and
probably outweigh the potential (low) risk of complications. opioids,66,87,88 of NSAIDs and acetaminophen,73,74 of acet-
Until further studies are performed, use in patients with car- aminophen and opioids,89 of acetaminophen and tramadol,90
diovascular risk factors should be cautious.72 and of a selective COX-2 inhibitor and gabapentin91 or pre-
Acetaminophen also possesses analgesic capability, both gabalin81 have been reported to have additive effects. At pres-
peripherally and centrally. Its analgesic effect is somewhat (about ent, information on other combinations (involving ketamine,
20 to 30%) weaker than those of conventional NSAIDs and clonidine, glucocorticoids, and other agents) is too sparse to
COX-2 inhibitors. For example, use of acetaminophen typically allow firm recommendations; however, multimodal analgesia
reduces morphine consumption by approximately 9 mg over a is undoubtedly promising, and multidrug combinations
24-hour period,61 which may be insufficient to significantly should certainly be explored further.
reduce opioid-related side effects or dramatically improve anal- The potential of combination regimens is especially intrigu-
gesia. However, acetaminophen lacks the side effects typical of ing with respect to the concept of perioperative opioid-sparing
NSAIDs.62 Combining acetaminophen with NSAIDs may analgesia. The use of one or several nonopioid analgesics in
improve analgesia, especially in smaller and moderate-sized such regimens may enhance recovery in that the concomitant
operations73,74; accordingly, this agent is recommended as a reduction in the opioid dosage will lead to decreased nausea,
basic component of multimodal analgesia in all operations. vomiting, and sedation.92–95 Both the adverse events associated
with postoperative opioid analgesia and the relatively high costs
other analgesics of such analgesia argue for an opioid-sparing approach.96,97 The
Glucocorticoids are powerful antiinflammatory agents and ability to reduce opioid-related and non–opioid-related side
have proven analgesic value in less extensive procedures,75,76 effects by use of multimodal analgesia may become especially
especially dental, laparoscopic, and arthroscopic operations. attractive for several reasons. First, there is growing evidence
In addition, they have profound antiemetic effects.77 Con- that the use of opioids as sole analgesics can lead to opioid-
cerns about possible side effects in the setting of perioperative induced hyperalgesia, whereby overstimulation of opioid recep-
administration have not been borne out by the results of ran- tors creates a nociceptive state (i.e., opioids increase sensitivity
domized studies.75,76 to painful stimuli).98 Also, in light of the JCAHO pain initiative
Tramadol is a weak analgesic that has several relatively and overall increased focus on reducing pain,1 a concern exists
minor side effects (e.g., dizziness, nausea, and vomiting) and that these initiatives may precipitate increased use of opioids
possesses weak opioid agonist activity and inhibits reuptake and thereby an increased risk of side effects.99,100
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Discussion
Physiologic Mechanisms of Acute Pain or augmentation of this descending system enhances analgesia.
The noxious stimuli from iatrogenic surgical injury or Epidural-intrathecal administration of alpha-adrenergic agonists
accidental trauma set a cascade of events in motion cumu- (e.g., clonidine) or of anticholinesterases (e.g., neostigmine)
lating in the perception of “pain.” Many interrelated com- works in this manner to provide pain relief.94
ponents contribute to the processing of nociceptive stimuli.
spinal reflexes
Clinicians should recognize that the neurobiology of noci-
ception is extremely complex, with multiple levels of redun- Nociception may be enhanced by spinal reflexes that affect
dancy, such that there is no “hardwired” or “final common” the environment of the nociceptive nerve endings. Thus,
pathway for the process of nociception of acute pain. The tissue damage may provoke an afferent reflex that causes
basic mechanisms are (1) afferent transmission of nocicep- muscle spasm in the vicinity of the injury, thereby increasing
tive stimuli through the peripheral nervous system after nociception. Similarly, sympathetic reflexes may cause
tissue damage, (2) modulation of these injury signals by decreased microcirculation in injury tissue, thereby generat-
control systems in the dorsal horn, and (3) modulation of ing smooth muscle spasm, which amplifies the sensation.
the ascending transmission of pain stimuli by a descending
control system originating in the brain [see Figure 1].101–103 postinjury changes in peripheral and
central nervous systems
peripheral pain receptors and neural
After an injury, the afferent nociceptive pathways undergo
transmission to the spinal cord
physiologic, anatomic, and chemical changes.102,103 These changes
Peripheral pain receptors (nociceptors) can be identified by include increased sensitivity on the part of peripheral nociceptors,
function but cannot be distinguished anatomically. The as well as the growth of sprouts from damaged nerve fibers that
responsiveness of peripheral pain receptors may be enhanced become sensitive to mechanical and alpha-adrenergic stimuli and
by endogenous analgesic substances (e.g., prostaglandins, eventually begin to fire spontaneously. Moreover, excitability
serotonin, bradykinin, nerve growth factor, and histamine), may be increased in the spinal cord, which leads to expansion of
as well as by increased efferent sympathetic activity.101 Anti- receptive fields in dorsal horn cells. Such changes may lower pain
dromic release of substance P may amplify the inflammatory thresholds, may increase afferent barrage in the late postinjury
response and thereby increase pain transmission. The periph- state, and, if normal regression does not occur during convales-
eral mechanisms of visceral pain are different from somatic or cence, may contribute to a chronic pain state.102
neuropathic nociception and likely involve transient receptor Neural stimuli have generally been considered to be the
potential vanilloid 1 receptors, acid-sensing ion channels, and main factor responsible for initiation of spinal neuroplasticity;
tachykinins.104 Peripheral opioid receptors have been demon- however, it now appears that such neuroplasticity may also be
strated to appear in inflammation on the peripheral nerve mediated by cytokines released as a consequence of COX-2
terminals but probably have little clinical relevance.31–33 induction.103 Improved understanding of the mechanisms of
Somatic nociceptive input is transmitted to the CNS through pain may serve as a rational basis for future drug development
A-delta and C fibers, which are small in diameter and either and may help direct therapy away from symptom control and
unmyelinated or thinly myelinated. Visceral pain is transmit- toward mechanism-specific treatment.107
ted through afferent sympathetic pathways; the evidence that In experimental studies, acute pain behavior or hyperexcit-
afferent parasympathetic pathways play a role in visceral noci- ability of dorsal horn neurons may be eliminated or reduced if
ception is inconclusive.104,105 the afferent barrage is prevented from reaching the CNS. Pre-
injury neural blockade with local anesthetics or opioids can
dorsal horn control systems and modula- suppress excitability of the CNS; this is called preemptive anal-
tion of incoming signals gesia. Although this has been a consistent finding in laboratory
All incoming nociceptive traffic synapses in the gray matter of studies, clinical studies have been less dramatic. A critical anal-
the dorsal horn (Rexed laminae I to IV). Several substances may ysis of controlled clinical studies that compared the efficacy of
be involved in primary afferent transmission of nociceptive stimuli analgesic regimens administered preoperatively with the effi-
in the dorsal horn: substance P, enkephalins, somatostatin, neu- cacy of the same regimens administered postoperatively con-
rotensin, g-aminobutyric acid (GABA), glutamic acid, angiotensin cluded that preemptive analgesia does not always provide a
II, vasoactive intestinal polypeptide (VIP), and cholecystokinin clinically significant increase in pain relief.108,109 Nonetheless, it
octapeptide (CCK-8).102,106 From the dorsal horn, nociceptive is important that pain treatment be initiated early to ensure
information is transmitted through the spinothalamic tracts to the that patients do not wake up with high-intensity pain.
hypothalamus, through spinoreticular systems to the brainstem
and reticular formation, and finally to the cerebral cortex.
Effects of Pain Relief
descending pain control system
s elected p hys iologic res p ons es to oper ation
A descending control system for sensory input originates in
the brainstem and reticular formation and in certain higher brain Cardiovascular
areas. The main neurotransmitters in this system are norepi- It has traditionally been thought that an imbalance of myo-
nephrine, serotonin, acetylcholine, and enkephalins. Stimulation cardial oxygen supply and demand, such as an increase in
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Perception of Pain
Trauma
Capillary
To the Limbic System Descending Inhibitory Pathway
Neurotransmitters at
Dorsal Horn Level:
Norepinephrine Release of
Serotonin Substance P
Enkephalins Histamine
Serotonin
Primary Afferent
Bradykinin
Neurotransmitter
Prostaglandins
Candidates
Substance P
Spinothalamic Tract L-Glutamate
GABA Release of
VIP
CCK-8 Sensory Nerve Norepinephrine
Somatostatin
Muscle
Motor of other Efferent Nerve
Segmental Reflexes:
Increased Skeletal Muscle Tension
Decreased Chest Compliance
More Nociceptive Input
Increased Sympathetic Tone
Decreased Gastric Mobility
IIeus, Nausea, Vomiting
Figure 1 Shown are the major neural pathways involved in nociception. Nociceptive input is transmitted from the periphery to
the dorsal horn via A-delta and C fibers (for somatic pain) or via afferent sympathetic pathways (for visceral pain). It is then
modulated by control systems in the dorsal horn and sent via the spinothalamic tracts and spinoreticular systems to the
hypothalamus, to the brainstem and reticular formation, and eventually to the cerebral cortex. Ascending transmission of
nociceptive input is also modulated by descending inhibitory pathways originating in the brain and terminating in the dorsal horn.
Nociception may be enhanced by reflex responses that affect the environment of the nociceptors, such as smooth muscle spasm.
CCK = cholecystokinin-octapeptide; GABA = γ -aminobutyric acid; VIP = vasoactive intestinal peptide.
demand (e.g., increase in heart rate or blood pressure) or a uncontrolled postoperative pain may be especially detrimen-
decrease in supply (e.g., decreased coronary blood flow to the tal and contribute to cardiac morbidity through activation of
vulnerable subendocardial areas), may contribute to periop- the sympathetic nervous system, other surgical stress
erative cardiac events, particularly in patients with decreased responses, and the coagulation cascade. Increased sympa-
cardiac reserve.110 Although many factors may contribute to thetic nervous system activity can increase myocardial oxygen
an imbalance of myocardial oxygen supply and demand, demand by increasing heart rate, blood pressure, and
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contractility or even decrease myocardial oxygen supply, other functions, including tissue repair, autoimmune
which, in turn, may lead to angina, dysrhythmias, and areas regulation, arteriosclerosis, and tumor growth and metasta-
of myocardial infarction.110 In addition, sympathetic activa- sis.114 Nevertheless, the primary components of the coagula-
tion may enhance perioperative hypercoagulability, which tion systems comprise cellular (e.g., platelets, endothelial
may contribute to perioperative coronary thrombosis or vaso- cells, monocytes, and erythrocytes) and molecular (e.g.,
spasm, thus reducing myocardial oxygen supply.111 coagulation factors and inhibitors, fibrinolysis factors and
inhibitors, adhesive and intercellular proteins, acute-phase
Pulmonary proteins, immunoglobulins, phospholipids, prostaglandins,
The pathophysiology of pulmonary dysfunction after sur- and cytokines) components.114 The normal process of coag-
gery is multifactorial. Relevant factors include disruption of ulation involves several steps, including initiation (damaged
normal respiratory muscle activity, which may result from vascular endothelium expresses tissue factor, which ulti-
either surgery or anesthesia, reflex inhibition of phrenic nerve mately leads to generation of thrombin), amplification (aug-
activity with subsequent decrease in diaphragmatic function, mentation of the effects of thrombin), propagation (formation
and uncontrolled postoperative pain, which may contribute of clot), and stabilization (formation of a stable fibrin mesh-
to voluntary inhibition of respiratory activity, or splinting.112 work that protects clot from fibrinolytic attack).114 However,
Although the pathophysiology of breathing and respiratory following surgery, the normal process of coagulation may
muscle function following surgery is complex, it is clear that become unbalanced, which may result in a tendency toward
anesthetic or analgesic agents administered in the periopera- thrombosis. Immediately after surgical incision, there are
tive period affect the central regulation of breathing and increases in the levels of tissue factor, tissue plasminogen
activities of respiratory muscles. This incoordination of respi- activator, plasminogen activator inhibitor–1, and von Will-
ratory muscle function (which may last well into the postop- ebrand factor, which contribute to a hypercoagulable and
erative period) will impair lung mechanics, increasing the risk hypofibrinolytic state postoperatively.114 Many of these det-
of hypoventilation, atelectasis, and pneumonia. Visceral stim- rimental responses may be reduced by excellent postopera-
ulation may decrease phrenic motoneuron output, which tive analgesia and in particular by the sympathetic and
results in a decrease in diaphragmatic descent and lung afferent block provided by thoracic epidural analgesia with
volumes.112 local anesthetics.
Gastrointestinal postoperative morbidity
Although decreased GI motility is expected after abdomi- Despite excellent theoretical reasons why high-quality
nal surgery, return of GI function usually occurs within sev- analgesia should improve postoperative physiology and out-
eral days postoperatively. Some patients will develop paralytic comes, the effects of nociceptive blockade and pain relief
ileus, a protracted and more severe state of GI immotility. on postoperative morbidity remain controversial.16 There
Although the pathophysiology of postoperative ileus and are several likely reasons why these effects are difficult to
decreased GI motility is multifactorial, the primary mecha- assess. Primarily, surgical techniques and perioperative care
nisms include neurogenic (spinal, supraspinal adrenergic are constantly evolving and improving, with subsequent
pathways), inflammatory (i.e., local inflammatory responses reduction in baseline morbidity and mortality. Thus, the
initiate neurogenic inhibitory pathways), and iatrogenic positive effects of analgesia on outcomes may be apparent
pharmacologic (e.g., opioids) mechanisms.113 In the acute only on selected high-risk patients or procedures. Several
postoperative phase, neurogenic (spinal and supraspinal) systematic reviews have examined this question and have
mechanisms are primary mediators of decreased GI motil- reached the following conclusions. For open major vascular
ity.113 Activation of splanchic afferents and increased sympa- and thoracic procedures, there is good evidence from sys-
thetic outflow, along with the possible use of opioids, are the tematic reviews and large randomized controlled trials that
predominant mechanisms for decreased GI motility immedi- thoracic epidural analgesia may reduce cardiovascular and
ately following surgery. However, over the subsequent post- pulmonary morbidity when compared with systemic opi-
operative days, a prolonged phase of postoperative ileus oids.16 There is good evidence from meta-analyses that
occurs. The presumed etiology of the latter is distinct and intraoperative spinal or epidural local anesthetics in lower-
involves an enteric molecular inflammatory response that body procedures reduce estimated blood loss by about
impairs local neuromuscular function and activates neuro- 30%.17,115 Finally, the duration of postoperative ileus is
genic inhibitory pathways.113 Our understanding of the reduced by approximately 24 to 36 hours with the use of
mechanisms of postoperative ileus is not complete, and it is epidural analgesia with local anesthetic–containing solu-
likely that these three mechanisms are not discrete phenom- tions after major open abdominal procedures.16 This effect
ena but interrelated. may be of major significance in that reduction of ileus
allows earlier oral nutrition,50 which has been demonstrated
Coagulation to improve outcome.
It is recognized that hypercoagulability occurs in associa- Another key feature in the difficulties assessing the impact
tion with surgical procedures. Although the pathophysiology of postoperative analgesia is that most studies to date have
of coagulation-related events (e.g., formation of deep vein focused on the effects of a single factor (i.e., epidural analge-
thrombosis has essentially been unchanged since Virchow’s sia) on overall postoperative morbidity. In current medical
initial description of the triad of stasis, blood vessel injury, practice, this is probably too simplistic an approach as overall
and hypercoagulability, our current understanding of the postoperative outcome is known to be determined by multi-
coagulation system is that it is a complex system with many ple factors.116–118 Besides postoperative pain relief, reinforced
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psychological preparation of the patient, reduction of stress nists, and anticonvulsant analgesia adjuncts such as gabapen-
by performing neural blockade or opting for minimal invasive tin.61,124,125 Future studies will need to define optimal strategies
procedures, and enforcement of early oral postoperative feed- for high-risk procedures and patients.
ing and mobilization may all play a significant role in deter-
mining outcome.118 Prevention of intraoperative hypothermia, barriers to effective postoperative analgesia
avoidance of fluid overloading, and avoidance of hypoxemia In general, multiple advisory and supervisory organizations
may be important as well.118,119 Therefore, although adequate (e.g., JCAHO, World Health Organization) recognize the
pain relief is obviously a prerequisite for good outcome, the importance of adequate pain control.1 Partially in response to
best results are likely to be achieved by combining analgesia these initiatives, there has been a marked increase in the cre-
with all of the aforementioned factors in a multimodal reha- ation and requirement of acute pain treatment services within
bilitation effort. hospitals across the world.126 Work continues on attempting
to create efficient and simple delivery techniques and tech-
development and prevention of chronic nologies for postoperative analgesia. In addition to economic
postoperative pain constraints, significant concerns regarding potential for opioid
Although not all nociceptive input results in a pathologic tolerance and addiction remain as a barrier.1 Continued expo-
process, a substantial percentage of patients who undergo sure of an opioid receptor to high concentrations of opioid will
certain surgical procedures will exhibit prolonged central cause tolerance. Tolerance is the progressive decline in an
sensitization and chronic pain [see Table 11]. Pathologic opioid’s potency with continuous use, so higher and higher
nociceptive input may cause central sensitization, which is concentrations of the drug are required to cause the same
marked by hyperexcitable spinal neurons that exhibit a analgesic effect. Physical dependence refers to the production
decreased threshold for activation, increased and prolonged of an abstinence syndrome when an opioid is withdrawn. It is
response to noxious input, expansion of receptive fields, defined by the World Health Organization as follows:
possible spontaneous activity, and activation by normally
A state, psychic or sometimes also physical, resulting from
non-noxious stimuli.120
interactions between a living organism and a drug, char-
Induction and maintenance of central sensitization empha-
acterized by behavioural and other responses that always
size different receptor-neurotransmitter combinations, includ-
include a compulsion to take the drug on a continuous or
ing NMDA receptors, prostaglandins, and neuropeptides
periodic basis in order to experience its psychic effects,
(substance P, calcitonin gene–related peptide, neurokinin A).121
and sometimes to avoid discomfort from its absence.127
Ultimately, transcriptional changes (including induction of
genes), structural changes in synaptic connections (e.g., con- This definition is very close to the popular concept of addic-
tact between low-threshold afferent and nociceptive neurons), tion. It is important, however, to distinguish addiction (imply-
and loss of inhibitory interneurons may result in a persistent ing compulsive behavior and psychological dependence) from
state of central sensitization.122 tolerance (a pharmacologic property) and from physical
Multiple studies and reviews have noted that more severe dependence (a characteristic physiologic effect of a group of
acute postoperative pain is a risk factor for development of drugs). Physical dependence does not imply addiction. More-
chronic postoperative pain.61,123 Although optimal strategies over, tolerance can occur without physical dependence; the
for prevention of chronic pain have not been identified, converse does not appear to be true. The possibility that the
promising modalities include preemptive regional analgesia medical administration of opioids could result in a patient
such as thoracic epidural local anesthetics, NMDA antago- becoming addicted has generated much debate about the use
Table 11 Approximate Incidences and Risk Factors for Development of Postoperative Chronic Pain
Surgical Procedure Incidence of Chronic Pain (%) Risk Factors
Thoracotomy 30–70 Increased acute pain
Open vs thoracoscopic
Not using thoracic epidural analgesia with local anesthetics
Intercostal nerve injury
Mastectomy 11–60 Increased acute pain
Increased acute opioid consumption
Immediate adjuvant radiation therapy
Axillary dissection vs sentinel node biopsy
Inguinal hernia repair 0–37 Increased acute pain
Preoperative pain
Female gender
Surgery for recurrent hernia
Open vs laparoscopic
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of opioids. In a prospective study of 12,000 hospitalized treatment techniques, the risks attendant on the procedures
patients receiving at least one strong opioid for a protracted under consideration, and the cost to the patient. It is to be
period, there were only four reasonably well-documented hoped that our growing understanding of basic pain mecha-
cases of subsequent addiction, and in none of these was there nisms and appropriate therapy, combined with the promising
a history of previous substance abuse.128 Thus, the iatrogenic data supporting the idea that adequate inhibition of surgically
production of opioid addiction is very rare. It is hoped that induced nociceptive stimuli may reduce postoperative mor-
continued physician and patient education will reduce this bidity, will stimulate more surgeons to turn their attention to
barrier to high-quality postoperative analgesia. this area. Effective control of postoperative pain, combined
with a high degree of surgical expertise and the judicious use
of other perioperative therapeutic interventions within the
Conclusion context of multimodal postoperative rehabilitation, is certain
The choice of therapeutic intervention for acute postopera- to improve acute and long-term patient outcomes.
tive pain is determined largely by the nature of the patient’s
problem, the resources available, the efficacy of the various Financial Disclosures: None Reported
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