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Strategies for effective postoperative pain

management
G. DIAZ, P. FLOOD
Department of Anesthesiology
Columbia University
New York, NY, USA
Postoperative pain management an important
clinical issue. The clinicians tool-bag remains
incomplete. Improvements in the management
of postoperative pain will ultimately translate
into the broader, safer application of surgical
procedures upon a wider patient population.
The application of multimodal therapy that
includes non-pharmacologic therapies, pre-
emptive therapies, and new medications for
the treatment of postoperative pain is an emerg-
ing concept that provides significant immedi-
ate as well as potential future advantages.
Key words: Pain, postoperative, diagnosis - Pain,
postoperative, therapy - Pain.
T
his decade (2001 to 2010) has been des-
ignated the Decade of Pain Control and
Research by the United States Congress.
1
While there have been significant advance-
ments in options for pain assessment and
therapy, effective postoperative pain man-
agement remains a frequent dilemma for
patients and clinicians. An estimated 70% to
80% of the 23 million Americans who under-
go surgical procedures each year report mod-
erate to severe pain in the immediate post-
operative period despite treatment with avail-
able analgesic medications.
2, 3
Unfortunately,
difficulty with postoperative pain perists as
over one-half of patients report continued
pain during the late postoperative period.
4
Effective pain management improves
patient satisfaction, decreases hospital stay,
and shortens recovery of the postsurgical
patient. The sequelae of inadequate postop-
erative pain management include: hospital
re-admission, prolonged hospitalization, com-
promised prognosis, and increased morbid-
ity secondary to immobility and pulmonary
dysfunction.
5, 6
Furthermore, there is evidence
in animals and increasingly in human studies
that the inadequate treatment of acute pain
leads to neuroplasticity favoring chronic pain
syndromes. ADDIN7 This review details cur-
rent therapeutic options as well as potential
strategies for the effective management of
early postoperative pain.
Pain management modalities
Therapeutic options for early postopera-
tive pain can be classified by route of admin-
istration or mechanism of action. Common
administration routes are oral, intravenous,
intramuscular, subcutaneous, rectal, trans-
dermal, intrathecal, and epidural. Parenteral
medications can be administered via an inter-
Vol. 72, N. 3 MINERVA ANESTESIOLOGICA 145
Address reprint requests to: G. C. Diaz, D.O., Department
of Anesthesiology, New York - Presbyterian Hospital, 622
West 168th St. Room PH5-505 New York, NY 10032 USA
E-mail: gd2046@columbia.edu
TERAPIA ANTALGICA
MINERVA ANESTESIOL 2006;72:145-50
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DIAZ STRATEGIES FOR EFFECTIVE POSTOPERATIVE PAIN MANAGEMENT

mittent or controlled delivery device.
Neuronal blocks include neuraxial blocks
and peripheral nerve blocks that are useful
adjuncts for the immediate management of
postoperative pain. Their application is lim-
ited by physiologic parameters (platelet func-
tion, coagulation), patient cooperation, and
skilled clinical staff. This review is limited to
enterally and parenterally administered med-
ications. Multimodal postoperative pain man-
agement incorporates the simultaneous use of
multiple analgesic techniques with different
mechanisms of action and adverse effect pro-
files. Its use is intended to capitalize on the
synergistic properties of analgesics and thus
lower the individual required dose and expo-
sure to an adverse effect.ADDINADDIN
Pharmacologic as well as non-pharmacolog-
ic modalities can be integrated.
The mechanism of action of commonly
used analgesics for acute postoperative pain
can be broadly subdivided into analgesic or
anti-inflammatory agents. Analgesics include
opioids and acetaminophen while non-
steroidal anti-inflammatory drugs (NSAIDs)
include a wide variety of agents with anti-
inflammatory action.
Opioids
Opioids are the most widely utilized and
versatile modality for postoperative pain man-
agement. Available methods of administra-
tion encompasses the entire spectrum includ-
ing oral, subcutaneous, intramuscular, intra-
venous, rectal, intrathecal, epidural, and trans-
dermal. Potency and duration of action are
equally as broad. Opioids are the only fully
efficacious modality for treating severe post-
operative pain. Their potential efficacy; how-
ever, is commonly limited by their side effects
of respiratory depression, sedation, nausea,
and constipation that make the patient or
practitioner prefer pain to their use. Opioids
are endogenous and exogenous substances,
available as a natural and synthetic product,
that bind specifically to opioid receptors to
stimulate an agonist effect.
10
Opioid receptors
are found in presynaptic and postsynaptic
sites in the central nervous system (CNS) and
outside the CNS in peripheral tissues.
11, 12
Morphine is a naturally occurring opioid that
is derived from opium and also available as
a synthetic agent. Morphine is also a natural
substance that can be found in the brain of
animals never exogenously exposed.
7
Morphine is the prototype opioid agonist that
is the standard for comparison (Table I). Semi-
synthetic opioids are produced from chemi-
cal modification of the morphine molecule
and include codeine, fentanyl, sufentanil,
alfentanil, and remifentanil. Synthetic opi-
oids represent de novo compounds that
include levorphanol, pentazocine, meperi-
dine, and fentanyl (Table II). Factors guid-
ing the clinical selection of a specific opioid
include potency, pharmacokinetics, and avail-
able route of administration. Increasing poten-
cy and duration of action avoids frequent
dosing schedules, volume of administration
and theoretically reduces the potential for
non-specific side effects.
While opioids are the principal therapy for
postoperative acute pain, their use is limited
146 MINERVA ANESTESIOLOGICA Marzo 2006
TABLE I.Potency of frequently utilized opioids (intra-
venous dosage).
Morphine 1.0
Meperidine 0.1
Hydromorphone 5
Fentanyl 75 - 125
Sufentanil 500 1 000
Alfentanil 25.0
TABLE II.Classification of opioid compounds.
Naturally occurring
Morphine
Codeine
Papaverine
Thebaine
Semisynthetic
Heroin
Dihydromorphone
Morphinone
Etorphine
Buprenorphine
Synthetic
Morphinan-derived (levorphanol)
Diphenylpropylamine-derived (methadone)
Benzomorphan-derived (pentazocine)
Phenylpiperdine-derived (fentanyl)
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STRATEGIES FOR EFFECTIVE POSTOPERATIVE PAIN MANAGEMENT DIAZ

by adverse reactions that range from tolera-
ble to incapacitating. Adverse effects com-
mon to all opioids include sedation, dose-
dependent depression of ventilation, consti-
pation, delayed gastric emptying, nausea,
vomiting, urinary retention, and pruritis.
10
Opioid-induced respiratory depression occurs
via a direct agonist effect upon respiratory
control neurons in the brainstem that de-
crease responsiveness to carbon dioxide and
displace the carbon dioxide response curve
to the right.
13
Elderly patients and patients
who are asleep are more prone to the venti-
latory depressant effects of opioids.
14
Opioids
lower respiratory rate and stimulate a com-
pensatory increase in tidal volume. Excessive
doses result in apnea; however, the patient
may initiate a breath in response to a com-
mand, thus apnea is not due to sedation.
10
Opioid-induced ventilatory depression, in
the presence of residual anesthetic effects
and atelectasis during the immediate post-
operative period, increases the risk of disor-
dered breathing and arterial desaturation.
15-17
Opioid-induced nausea and vomiting occur
via direct stimulation of the chemoreceptor
trigger zone in the floor of the fourth ventri-
cle. This adverse effect is not dose-depen-
dent and can be incapacitating for the patient.
Dopaminergic receptors located in the
chemoreceptor trigger zone modulate this
effect and account for the anti-emetic effica-
cy of butyrophenones.
10
Opioids offer wide flexibility with respect
to administration. All are available for enter-
al and parenteral administration. Fentanyl is
also available as a transdermal patch and as
a lollipop for transmucosal delivery.
Parenteral administration may involve injec-
tion by healthcare personnel or be patient-dri-
ven by an intermittent, intravenous delivery
device termed Patient Controlled Analgesia
(PCA). PCA is a frequent modality for the
management of postoperative pain. Docu-
mented advantages of PCA are greater patient
satisfaction, empowerment of the patient to
control their analgesia, absence of waiting
time for the provider to obtain and adminis-
ter the medication, attainment of a steady
level of analgesia, less postoperative pul-
monary complications, better pain relief, and
faster recovery.
18, 19
Adverse effects inherent
to the specific opioid being utilized limit
application. While substantial literature exists
on the application of PCA, no convincing
data exist on efficacy or frequency of adverse
effects to recommend a specific opioid.
Opioids can be administered in combina-
tion with a different class of analgesic drug.
This capitalizes on additive analgesic effects
while minimizing the potential adverse effects
of opioids. NSAIDs augment the analgesic
properties of opioids and a regular dosing
schedule achieves more consistent analge-
sia, avoids unnecessary suffering, and
improves patient satisfaction. Potentiation of
opioid action by NSAIDs may result from the
increased conversion of arachidonic acid to
lipoxygenase products that facilitate opioid
effects upon potassium channels.
20
An opi-
oid-sparing strategy is the foundation for
the analgesic ladder concept for pain man-
agement proposed by the World Health
Organization.
21
As increased pain is observed,
the potency and frequency of opioid and
adjuvant medications are escalated to obtain
a desired outcome.
22
Adjuvants
Adjuvant analgesic medications can pro-
vide synergistic effects in combination with
opioids thereby lowering overall opioid uti-
lization and decreasing potential adverse
effects.
23-25
NSAIDs are a principal adjunct
during general anesthesia and monitored
anesthesia care as well as postoperative pain
analgesia.
26
NSAIDs are not adequately effi-
cacious as sole agents for immediate control
of severe postoperative pain as they exhibit
a ceiling effect when utilized for postopera-
tive analgesia.
23
Preoperative administration of NSAIDs can
decrease postoperative pain and opioid
requirements, particularly after ambulatory
surgical procedures.
23, 26
With respect to anal-
gesia in the immediate postoperative peri-
od, preoperative intravenous administration
is more efficacious than intramuscular admin-
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istration, whereas oral administration is asso-
ciated with improved analgesia in the later
recovery period. When used in combination
with a short-acting opioid and local anes-
thetics, NSAIDs also improve analgesia in the
postoperative period. These data are most
impressive when ketorolac is the agent
administered. Ketorolac (30 mg) produces
analgesia equivalent to 10 mg of morphine or
100 mg of meperidine without ventilatory,
cardiovascular, or central nervous system
effects. Furthermore, ketorolac does not affect
bowel, bladder, or biliary smooth muscle
activity. Maximal plasma concentration occurs
rapidly with a half-life of approximately 5
h.
27
Studies involving ambulatory surgical
procedures in adults and children have con-
sistently demonstrated improved analgesia
and patient satisfaction with lower opioid
requirements and a reasonable adverse effect
profile.
28-30
NSAIDs come in a variety of chem-
ical classes (Table III). As a group, they pos-
sess analgesic, anti-inflammatory, and anti-
pyretic effects. Their principal mechanism of
action is inhibition of cyclooxygenase there-
by decreasing prostaglandin synthesis.
Inhibition of prostaglandin synthesis reduces
the inflammatory response to surgical trauma
and decreases peripheral nociception and
pain perception. NSAID doses required to
inhibit inflammation exceed that required to
inhibit prostaglandin synthesis suggesting
additional mechanisms of action for their
anti-inflammatory effects. Enhanced T cell
suppressor activity, neutrophil aggregation
and adhesion, superoxide generation, and
suppression of rheumatoid factor production
have already been implicated.
27, 31
NSAIDs are well absorbed from the gas-
trointestinal tract, have low first-pass hepat-
ic extraction, are highly bound to plasma
albumin, and exhibit small volumes of dis-
tribution. As with any medication, their use is
also limited by potential adverse effects.
Adverse reactions to NSAIDs are common
and the reported spectrum is wide, mainly
involving gastrointestinal, hematologic, or
renal function. Skin and CNS reactions are
also reported. Blood dyscrasia, erythema mul-
tiforme, urticaria, pneumonitis, aseptic menin-
gitis, hepatic dysfunction, and aplastic anemia
have been rarely reported.
27, 31
Prostaglandin synthesis is critical to the
maintenance of normal gastrointestinal phys-
iology. Chronic NSAIDs use interferes with
normal gastrointestinal function resulting in
mucosal inflammation, erosion, ulceration,
hemorrhage, and perforation. NSAID-induced
renal toxicity also results from inhibition of
prostaglandin synthesis. Prostaglandins par-
ticipate in autoregulation of renal blood flow,
glomerular filtration, and influence tubular
transport. Inhibition of prostaglandin syn-
thesis results in renal medullary ischemia and
necrosis. NSAID-induced nephrotoxicity is
antagonized by hypovolemia, pre-existing
renal disease, congestive heart failure, sepsis,
intravenous contrast, diabetes, cirrhosis or
the presence of additional nephrotoxic med-
ication.
32
Selective inhibitors of the cyclooxygenase-
2 enzyme are specifically designed to inhib-
it the COX-2 isoenzyme that produces the
prostaglandins principally responsible for
pain, inflammation, and fever without inhibit-
ing the constitutive COX-1 isoenzyme. COX-
2 inhibitors have the advantages of lower
gastrointestinal adverse effects and lack an
anti-platelet effect.
27, 31, 32
This class of NSAIDs
demonstrate tremendous promise in the man-
agement of acute and chronic pain
33, 34
and
have an important role in extending the use
of balanced, multimodal analgesia to a broad
surgical population; however, several drugs
in this class have been voluntarily withdrawn
from the market because of concerns about
their cardiovascular risk profile.
35
The risk of
cardiovascular events has been found to be
elevated in some trials conducted with these
drugs. The only trial that has shown an ele-
vated risk of thrombotic events with acute
148 MINERVA ANESTESIOLOGICA Marzo 2006
TABLE III.Chemical classification of nonsteroidal
antiinflammatory drugs.
Carboxylic Acids
Acetylated Aspirin
Non-Acetylated Difunisal
Acetic Acids Indomethacin
Propionic Acids Ibuprofen
Enolic Acids Piroxicam
Pyrrolopyrrole Ketorolac
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perioperative use of COX-2 inhibitors was

conducted in patients undergoing cardiac
surgery. All other trials have demonstrated
increased risk only with chronic use of these
agents.
36
Acetaminophen is a useful alternative to
NSAIDs as an analgesic and antipyretic.
Unlike NSAIDs, acetaminophen does not pro-
duce gastric irritation or affect platelet aggre-
gation. Anti-inflammatory effects of aceta-
minophen are minimal as there is minimal
affect on prostaglandin synthesis outside the
central nervous system. Conversely, strong
central inhibition of prostaglandin synthesis
confers acetaminophens analgesic and
antipyretic effects. Systemic absorption of
acetaminophen is rapid and efficient after
oral absorption without significant binding
to serum proteins. Metabolism is through
hepatic conjugation and hydroxylation to
inactive metabolites with only trace amounts
of drug excreted unchanged. Toxicity is man-
ifest by a metabolite, p-aminophenol, that
rapidly depletes intracellular glutathione
stores within hepatocytes and is concentrat-
ed in the hypertonic renal papillae. Hepatic
necrosis and fulminant hepatic failure may
accompany a single dose of acetaminophen
exceeding 15 g. Irreversible nephrotoxicity is
a frequent companion of acetaminophen-
associated liver failure.
27, 31
Novel therapies
Nicotine has demonstrated analgesic prop-
erties in animal studies
37, 38
and human vol-
unteers.
39, 40
The anti-nociceptive effect of
nicotine is thought to result from the activa-
tion of presynaptic nicotine receptors that
increase the release of native inhibitory pain
modulators including norepinephrine and
serotonin.
37
Importantly, for potential use in
a combined analgesic paradigm, nicotine has
side effects that are mostly opposite those of
opioid agonists. These include stimulant
properties and the enhancement of ventila-
tory drive.
41
One exception is that nicotine
has antiemetic action in smokers, but can
induce nausea in non-smokers. Data derived
from human volunteers have demonstrated
nicotine has analgesic effects in experimen-
tal paradigms of thermal and electrically
evoked pain in smokers as well as non-smok-
ers.
39
A recent clinical study among women
undergoing gynecological surgery evaluated
the effect of intranasal nicotine on postop-
erative pain and opioid utilization.
42
The
authors demonstrated lower pain scores,
reduced opioid utilization, and lower systolic
blood pressure among women receiving nico-
tine versus placebo. These results are cur-
rently being studied in a larger patient pop-
ulation undergoing various surgical proce-
dures.
Riassunto
Strategie per il trattamento efficace del dolore post-
operatorio
Il trattamento del dolore post-operatorio rimane un
importante problema clinico. La borsa degli strumenti
a disposizione del medico non ancora completa. I
miglioramenti nel trattamento del dolore post-ope-
ratorio comporteranno di conseguenza ad una pi
completa e pi sicura applicazione delle procedure
chirurgiche su un gruppo sempre pi esteso di pazien-
ti. Lapplicazione di molteplici e diverse terapie che
includono strategie non-farmacologiche, strategie
preventive e nuovi farmaci per il trattamento del dolo-
re post-operatorio un concetto emergente che for-
nisce sia una vantaggio significativo immediato che
potenziali futuri benefici.
Parole chiave: Dolore postoperatorio, diagnosi -
Dolore postoperatorio, terapia - Dolore.
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