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100 Phoon Ping CHEN, Christopher Ping Wing CHU, Edmond Kin Nam CHUNG
exhibit a lower propensity for gastrointestinal and
other side effects including adverse effects on the
kidneys and platelets [123, 259].
Non-steroidal anti-inflammatory drugs, including
COX-2 inhibitors, are contraindicated in patients
who are on anticoagulant therapy, have bleeding
diathesis, moderate to severe renal impairment,
allergy to an NSAID and a history of gastrointestinal
ulcer and/or haemorrhage. ey should be used
with caution in patients who are elderly or have
asthma and in individuals with a contracted
circulatory volume (e.g. haemorrhage, sepsis, pre-
eclampsia, cirrhosis and nephrotic syndrome).
A contracted circulatory volume predisposes the
patient on NSAIDs to acute renal failure [40].
However, a recent systematic review did not find
any significant adverse effect on postoperative renal
function in patients with normal pre-operative
renal function [147].
Selective COX-2 inhibitors rofecoxib and valdecoxib
were withdrawn from the market recently as they
were found to be associated with increased risk of
thrombotic events [31, 105, 204] and prompted
the Food and Drug Administration (FDA) in
the US to revise the labelling requirement for all
NSAIDs [281]. Other COX-2 inhibitors have also
been shown to have an increased risk of adverse
cardiovascular events after coronary artery bypass
graft [202, 204] and association with Steven-
Johnson syndrome/toxic epidermal necrolysis
[145]. Lumiracoxib was also withdrawn from the
market in Australia, Europe and other countries in
2007 after reports of liver adverse effects.
Administration of NSAIDs and paracetamol
Non-steroidal anti-inflammatory drugs can be
applied topically to the skin. Ibuprofen, ketoprofen
and piroxicam have been shown to be effective
in pain relief for soft tissue injury [185]. Topical
application of ibuprofen may be better than oral
administration as a high concentration of the drug
is found in the subcutaneous tissues and muscles
directly beneath [272]. Also, NSAIDs have been
employed in wound infiltration but the evidence of
efficacy via this route is equivocal [240].
e oral route is the commonest way to give
NSAIDS. Both oral NSAIDs and COX-2
inhibitors have been proven effective, such as
aspirin [79], ibuprofen [57], diclofenac [17, 57],
piroxicam [76], celecoxib [18], naproxen [166] and
ketorolac [264]. Paracetamol has been shown to be
an effective oral analgesic [16, 182]. It is also an
effective adjunct and can reduce the consumption
of opioids postoperatively [239].
In the suppository form, both paracetamol and
NSAIDs are effective in treating acute pain via the
rectal route [239]. In general, NSAIDs given rectally
may decrease gastric complication. However, the
sparing effect varies among different NSAIDs;
for example, rectal naproxen is probably safer
than indomethacin [110, 151]. For paracetamol,
comparing the same dose given orally, the rectal
route is slower in onset and less effective [4]. Rectal
absorption of paracetamol varies from 24–98%.
For children, the loading dose of paracetamol may
be as high as 40 mg/kg [143] and the maximum
recommended dose is 90 mg/kg/day; in neonates it
is 60 mg/kg/day [117].
ere are a few injectable forms of NSAIDs,
e.g. ketorolac, ketoprofen, indomethacin and
diclofenac. Intravenous ketorolac and parecoxib
are also effective in treating acute pain [19, 264].
Overall, the efficacy of IV NSAIDs has not been
found to be superior to that of the oral and rectal
routes [275].
Propacetamol, a prodrug of paracetamol (via esterase
hydrolysis), is injectable and can be converted to
paracetamol (2 g propacetamol is equivalent to 1
g paracetamol) in plasma within 7 minutes. e
disadvantages of propacetamol are that it needs to
be reconstituted before injection and may cause
contact dermatitis and pain on injection [93, 282,
284]. Recently, the injectable form of paracetamol
has also become available. e onset of analgesia
occurs within 5 to10 minutes and its efficacy is
proven [126, 239]. Intravenous paracetamol dosage
is similar to that of the oral route: 1000 mg every 4
to 6 hours for adults to a maximum dose of 4 g per
day. For children, the dose is 15 mg/kg given up to
four times per day.
Opioids
Detailed pharmacology of opioids is beyond the
scope of this chapter and is presented in relevant
pharmacology texts and in Chapter 21.
In the acute pain setting, in order to achieve
effective pain relief with minimal adverse effects, it
is necessary to individualise and titrate doses of the
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Acute Pain Management 101
Table 8.06 Guidelines for use of NSAIDs for
treatment of acute pain
Drug Routes Recommended adult
dose
Paracetamol Oral 10–15 mg/kg q4h po
Not exceeding 4000
mg/day
Ketorolac IV, IM, oral 30–60 mg IM bolus
followed by 10 mg
q6–8h
or 15–30 mg q6h po
Max 5 days
Diclofenac IM, oral,
rectal
50–100 mg q6–12h
Ketoprofen IM, oral,
rectal
25–75 mg q6–8h
Indomethacin IM, oral 25 mg q8–12h
Piroxicam IM, oral,
rectal
10 mg q12h
Naproxen Oral, rectal 500 mg initially
followed by
250 mg q8–12h (5
mg/kg q12h)
Ibuprofen Oral, rectal 400 mg q4–6h (10
mg/kg)
Diflunisal Oral 1000 mg initially
followed by 500 mg
q8–12h
Sulinac Oral 150–200 mg q12h
Meloxicam Oral, rectal 7.5–15 mg q24h
Parecoxib IV, IM 20–40 mg q6–12h
Max 80 mg/day
Celecoxib Oral 100–200 mg q12 h
Etoricoxib Oral 60–120 mg daily
opioid. e selection of opioid is generally heavily
influenced by pharmacokinetic considerations,
including the onset and duration of action of
the particular drug. Fentanyl, alfentanil and
sufentanil are more lipid-soluble and are potent
opioid agonists with a faster onset of action than
morphine or pethidine. e small volume of
distribution of alfentanil (also its low pKa) and
sufentanil is responsible for their rapid onset and
short duration of action. ey have been used in
patient-controlled analgesia but remain unpopular
in postoperative pain management because of their
brief action. Remifentanil is a newer opioid agonist
with a small volume of distribution, an ultra-short
half-life and duration of action and a short context-
sensitive half-life, making it a suitable opioid for
prolonged continuous infusion during surgery
[214]. However, remifentanil is not suitable for
postoperative pain management, as its high risk
of respiratory depression counteracts its advantage
when given as an infusion.
Morphine is the most commonly used opioid for
postoperative and trauma pain. In some parts of the
world, pethidine is still commonly used although
others have advocated its inappropriateness for use
as a first-line opioid analgesic for the treatment of
severe pain. ere appears to be a misconception
that pethidine may be less addictive and is
associated with less risk of respiratory depression
than morphine. Pethidine should be reserved for
brief courses in otherwise healthy patients who
have demonstrated unusual or adverse reactions
to other opioids such as morphine. Norpethidine
is a toxic metabolite of pethidine with a half-life
of 15 to 20 hours in patients with normal renal
function [111]. e half-life is greatly extended
in the elderly and in patients with impaired renal
function. Accumulation of norpethidine occurs
in prolonged administration and causes central
nervous system (CNS) excitation and may result
in dysphoria, irritable mood, tremors, twitchings,
myoclonus and convulsion [132].
Methadone is a synthetic opioid with high
oral bioavailability [111]. However, the long
half-life of 15 to 55 hours increases the risk of
accumulation of the drug and renders methadone
unsuitable for acute pain management. In drug
addicts on methadone therapy, a single daily dose
is possible.
Codeine is a weak opioid and is only suitable for
mild to moderate pain. A major proportion of
its analgesic effect results from its metabolism to
morphine. ere may be great inter-individual
variation in efficacy. It has been popular in the
treatment of postoperative pain in children,
although its use for this reason has recently been
examined [304].
Dextropropoxyphene is related structurally
to methadone and at equianalgesic doses the
incidence of side effects would be similar to
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102 Phoon Ping CHEN, Christopher Ping Wing CHU, Edmond Kin Nam CHUNG
those of codeine. It has an average half-life of 6
to 12 hours and is effective for mild to moderate
pain. A dose of 90–120 mg of propoxyphene
hydrochloride administered orally would equal the
analgesic effects of 60 mg of codeine, a dose that
usually produces about as much analgesia as 600
mg of aspirin [111]. Propoxyphene products were
withdrawn in the UK in 2007, and an FDA panel
recently (2009) advised that they should be banned
in the US. Propoxyphene compounds have been
associated with an increased risk of cardiac adverse
effects, addiction and accidental overdose.
Oxycodone is a semi-synthetic opioid and can be
administered orally, intranasally, intravenously
and intramuscularly. Although oxycodone’s
analgesic potency is similar to morphine, its higher
oral bioavailability renders its oral potency 1.5
to two times that of oral morphine. While the
immediate release preparation is used in acute
pain management, the controlled release form
is commonly used for a variety of chronic pain
conditions [134]. A fixed combination preparation
of oxycodone/paracetamol is also available and it
is one of the most frequently prescribed analgesics
in the US.
Hydromorphone is a semi-synthetic mu-opioid
agonist that is about five times as potent as morphine.
After oral ingestion, hydromorphone undergoes
extensively first-pass metabolism (bioavailability
of 30–35%) and is excreted in the urine. It has
been known to be metabolised to metabolites
that are associated with neuroexcitatory states
and other toxicity [191]. Hydromorphone can
be administered through oral, IV, subcutaneous,
epidural, intranasal, intrathecal and rectal routes.
Like oxycodone, immediate release and slow
or extended release preparations are available.
Extended release formulation may be associated
with higher overdose potential when taken with
alcohol or sedative agents.
Oxymorphone is another semi-synthetic mu-opioid
agonist, structurally similar to hydromorphone. It
is six to eight times more potent than morphine.
Immediate release and long acting formulations
are available, making oxymorphone an alternative
option in treating moderate to severe pain [226].
Agonist-antagonists such as buprenorphine and
butorphanol have also been used for postoperative
pain relief. However, these drugs exhibit a ceiling
effect in their analgesic efficacy and are only suitable
for moderate pain.
Tramadol is a synthetic analogue of codeine
and has a relatively low affinity for mu-opioid
receptors with a plasma elimination half-life of
5 to 6 hours. e efficacy of tramadol for the
management of moderate to severe postoperative
pain has been demonstrated in both inpatients
and day surgery patients undergoing a wide range
of surgical procedures [173, 247, 255]. Both
its oral and parenteral preparations (including
patient-controlled analgesia) have been used for
the treatment of postoperative pain. e dosing
regimen for postoperative use is 100 mg bolus with
further doses of 50 mg every 10 to 20 minutes as
necessary up to a total dose of 250 mg, followed by
subsequent doses of 50–100 mg every 4 to 6 hours
up to a maximum of 600 mg [247]. Tramadol
has a relative lack of respiratory depressant and
constipating effects compared with conventional
opioids such as morphine, and does not share the
propensity of non-steroidal anti-inflammatory
drugs to provoke asthma, gastrointestinal irritation
and renal impairment. It also has a low potential
for abuse or dependence. Adverse effects occur in
about 6% of patients, most commonly dizziness,
nausea, vomiting, somnolence, dry mouth, sweating
and headache. ere may be drug interaction
with coumarin anticoagulants, while seizure may
also occur, especially in patients who are taking
concomitant epileptogenic medications, selective
serotonin re-uptake inhibitors and neuroleptics,
and those with a history of alcohol abuse, stroke,
or head injury [39, 101, 238, 274].
Tramadol is also associated with serotonin syndrome,
a clinical condition that occurs as a result of an
iatrogenic drug-induced increase in intrasynaptic
serotonin levels [271]. e clinical manifestations
consists of a triad of neuromuscular hyperactivity,
autonomic hyperactivity and altered mental status,
and are characterised by clonus, hyper-reflexia,
hyperthermia and agitation. Although the majority
of cases improve with symptomatic and supportive
care, severe cases need intensive care and frequently
require mechanical ventilation. Caution should be
taken when tramadol is prescribed together with
MAOIs, selective serotonin re-uptake inhibitors,
antidepressants such as tricyclic antidepressants,
some opioids including pethidine, methadone and
propoxyphene, which are weak serotonin re-uptake
inhibitors [103, 129].
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Acute Pain Management 103
Recently, slow release tramadol and a tramadol/
paracetamol combined preparation have also
become available. is latter preparation may be
used for moderate pain or as co-analgesic, and is an
alternative to NSAIDs.
Most opioids produce a dose-related analgesia,
sedation and unconsciousness. Other side effects
of opioids include respiratory depression, dizziness,
nausea, vomiting, itchiness, urinary retention,
constipation, biliary spasm and rarely convulsion.
Level of consciousness should be monitored closely as
excessive sedation is an early sign of opioid overdose,
occurring before a decrease in respiratory rate.
Naloxone can be given to treat respiratory
depression and intractable pruritis induced by
opioids. Naloxone possesses no agonist activity
and is a competitive antagonist at the opioid
receptors. A single IV dose of 0.4 mg antagonises
the effect of morphine for only 60 to 90 minutes
[235]. Repeated doses or a continuous infusion
of naloxone is required for adequate and effective
reversal. When reversing opioid side effects such as
over-sedation and respiratory depression, naloxone
should be administered in small bolus doses, as rapid
correction may lead to sudden sympathetic rebound
responses, such as tachycardia, hypertension,
arrhythmias and pulmonary oedema.
Opioid tolerance and physiological dependence are
uncommon when the drug is used appropriately in
opioid naive patients for postoperative pain relief
and after trauma. In patients on long-term opioid
therapy, respiratory depression is unlikely because
tolerance develops after chronic use. Psychological
dependence and addiction are extremely unlikely
to develop after the use of opioid for acute pain
[222]. Although more commonly associated with
chronic opioid use, opioid-induced hyperalgesia
may occur in postoperative patients [5]. Clinicians
should suspect this phenomenon when opioid
treatment becomes ineffective in the absence of
disease progression, and when there is unexplained
pain exacerbation [54].
Administration of opioids
Oral opioids are commonly used in acute pain
management. Often, less potent opioids such as
dextropropoxyphene (65 mg) and oxycodone (5 mg
and 10 mg) and codeine (60 mg) are combined with
paracetamol in order to achieve adequate analgesic
effect [56, 77, 182]. A higher dose of oxycodone,
15 mg, is an effective analgesic on its own [78].
Tramadol and morphine (immediate release) are
two other effective oral treatments for acute pain
[170, 184]. e route of administration, dose and
frequency of commonly prescribed opioids are
shown in Table 8.07.
Intramuscular opioids are effective analgesics and
commonly employed for treating moderate to severe
acute pain [174, 264]. Intramuscular tramadol also
provides effective analgesia and there is evidence
that its use in controlling labour pain is similar to
that of pethidine [84]. Subcutaneous injection is
also effective as the absorption of morphine via this
route is similar to that of IM injection [250]. It
is important to prescribe round-the-clock regular
injections if IM or SC administration is considered
in the first 24 hours after an operation. is is
because pain is expected in the initial postoperative
period and on-demand prescription of IM or SC
opioid is usually inadequate.
Intravenous boluses of opioids are a less popular
choice as monitoring of side effects in the general
ward setting is labour-intensive. However, in
the recovery room with adequate staff who are
properly trained, small boluses of opioids can
be given as required both safely and effectively
[11]. Continuous IV infusion of opioid is usually
prescribed only for patients in areas where a high
level of nursing supervision is available, such as
recovery rooms, high dependency areas or intensive
care units. Variable patient requirement and the
risk of opioid overdose warrant closer monitoring
of patients’ conscious level and respiratory status.
is method is often reserved for patients who
are of very young age, mentally retarded, unco-
operative and when other techniques of pain relief
are contraindicated [85, 223]. When continuous
infusion is required, it is also worth noting that
continuous SC infusion of diamorphine is as
effective as IV infusion [249]. A popular method
of administering IV opioid is through patient-
controlled analgesia. More details can be found
later in the chapter.
Administration of neuraxial opioids is a common
practice for acute pain control. In general,
hydrophilic opioids (e.g. morphine) have a slower
onset, longer duration of action and more cephalic
spread compared with lipophilic opioids (e.g.
fentanyl), when administered either intrathecally
or epidurally.
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104 Phoon Ping CHEN, Christopher Ping Wing CHU, Edmond Kin Nam CHUNG
e safety and efficacy for intrathecal morphine,
fentanyl and sufentanil are well established.
Typical intrathecal dosages in adults are 0.1–0.3
mg for morphine, 5–10 mcg for sufentanil and
20–30 mcg for fentanyl [231]. e duration of
analgesic effect for intrathecal morphine is 18
to 24 hours, 1 to 4 hours for fentanyl and 2 to
6 hours for sulfentanil. It should be warned
that lipophilic opioids may spread rostrally and
respiratory depression has been reported to occur
within 5 to 20 minutes of intrathecal sufentanil
administration [88]. In comparison, there is
limited evidence for pethidine and methadone
in terms of efficacy. Furthermore, even though
pethidine exhibits local anaesthetic effects as well,
its use intrathecally is limited by a high incidence
of nausea and vomiting [230].
Various opioids have been administered into the
epidural space, e.g. morphine, fentanyl, pethidine,
hydromorphone, diamorphine, sufentanil and
alfentanil. In general, this procedure is more
effective when combining local anaesthetic and
opioid than when using each drug alone [62, 290].
Details of epidural opioids can be found later in
this chapter.
Fentanyl, butorphanol and pethidine are effective
when administered intranasally [1, 205, 268, 269].
Sublingual buprenorphine has been shown to be
effective in the postoperative setting [63, 177].
Although oral transmucosal fentanyl citrate has
been found effective in controlling postoperative
pain [7, 150], there is still a lack of data to fully
support its role in the management of acute pain.
While transdermal fentanyl is not suitable for
acute pain management because of its slow onset
and offset of action, wide clinical variability and
high incidence of respiratory depression [41, 218,
243], the recent development in iontophoresis
technology may provide a promising future for
Table 8.07 Guidelines for the use ofopioids in the treatment of acute pain
Opioid Route of administration Recommended initial
dose (mg/kg)
Frequency
Morphine Oral
SC, IM, IV
0.5
0.15
Q3-4h
Q3-4h
Pethidine Oral
SC, IM, IV
2.5–3.5
1.5–2.0
Q2-3h
Q3h
Fentanyl IV 0.0008–0.0016 Cont. infus. PCA
Alfentanil IV 0.03–0.05 Cont. infus. PCA
Sufentanil IV 0.0001–0.0003 Cont. infus. PCA
Methadone Oral
SC, IM, IV
0.2–0.4
0.15
Q6–8h
Q6–8h
Hydromorphone Oral
SC, IM
0.03–0.08, short-acting
0.015
Q3–6h
Q3–6h
Oxycodone Oral
SC, IM, IV
0.1–0.2
0.05
Q3–4h
Q3–4h
Codeine Oral
SC, IM
1.5
1.0
Q3–4h
Q3–4h
Buprenorphine Sublingual
SC, IM, IV
0.2–0.4 mg/dose
0.0025
Q6–8h
Q6–8h
Butorphanol Transnasal
SC, IM, IV
0.025
0.01–0.03
Q3–4h
Q3–4h
Tramadol Oral
IM, IV
50–100 mg/dose
Loading dose up to 250
mg then 50–100 mg/dose
Q4–6h
Q4–6h
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Acute Pain Management 105
a patient-controlled transdermal system with
fentanyl [286].
Many opioids have been used in perineural injection
together with local anaesthetics, e.g. alfentanil,
fentanyl, morphine and tramadol. However, the
benefits are probably minimal [189]. Morphine is
also commonly injected intra-articularly, but the
effect is controversial and the current evidence does
not support its analgesic effect in knee arthroscopy
[242].
Local anaesthetic agents
Bupivacaine is commonly used in postoperative
analgesia and acute pain relief. Lignocaine
is commonly used for regional anaesthesia,
but it is not suitable for continuous infusion
postoperatively because of tachyphylaxis, often
necessitating an increasing amount of drug to
control the same level of pain [44]. Ropivacaine
has an improved cardiovascular toxicity profile
and higher threshold for CNS toxicity compared
with racemic bupivacaine [168, 169]. Ropivacaine
also exhibits differential sensory-motor blockade
allowing sensory blockade without significant
motor dysfunction.
Levo-bupivacaine is the S (−)-enantiomer of racemic
bupivacaine, and is a long-acting local anaesthetic
with a dose-dependent duration of anaesthesia
[95]. It also possesses a lower risk of cardiovascular
and CNS toxicity, and has less negative inotropic
effect than bupivacaine. e sensory block tends to
be 23 to 45 minutes longer with levo-bupivacaine
after epidural administration and approximately 2
hours after peripheral nerve block when compared
with similar doses of bupivacaine. With epidural
administration, levo-bupivacaine also produces less
prolonged motor block than sensory block.
Toxic levels may be reached during the use of
excessive doses of local anaesthetic for regional
anaesthesia when systemic absorption is high, or
when accidental intravascular injection occurs.
Features of local anaesthetic toxicity include
numbness in the tongue and mouth, dizziness,
tinnitus, diplopia, drowsiness, convulsion, coma,
respiratory depression and cardiovascular system
(CVS) depression. e use of a low dose of local
anaesthetic for postoperative analgesia is not
usually associated with this problem. Side effects
of local anaesthetic are often related to the route
of delivery. Regional infusion of local anaesthetic
to a nerve plexus may be associated with muscle
Table 8.08 Local anaesthetics used in acute pain relief [234]
Local anaesthetic
(LA)c
% LA solution for
analgesia block
Duration of action
(hour)
% LA solution for
analgesia infusion
Special remarks
Lignocaine
Infiltration
Plexus or nerve
Epidural
0.5–1
0.75–1.5
1–2
1–2
1–3
1–2
0.5–1
0.5–1
0.25–0.5
Rapid onset. Not
commonly used for
continuous regional
infusion because of
acute tolerance
Bupivacaine
Infiltration
Plexus or nerve
Epidural
0.125–0.25
0.25–05
0.25–05
1.5–6
8–24
1.5–5
0.125–0.25
0.125–0.25
0.0625–0.125
Systemic
overdosage may
cause ventricular
arrhythmias, e.g.
resistant ventricular
fibrillation and CVS
collapse
Ropivacaine
Infiltration
Plexus or nerve
Epidural
0.5–0.75
0.5–0.75
0.5-0.75
2–6
2–6
3–5
0.2
0.2
0.1–0.2
Improved CVS
and CNS toxicity;
differential sensory-
motor blockade at
lower concentration
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106 Phoon Ping CHEN, Christopher Ping Wing CHU, Edmond Kin Nam CHUNG
weakness and paraesthesia, while hypotension may
occur during epidural administration. Specific side
effects for the different local anaesthetic agents are
mentioned in Table 8.08.
Administration of local anaesthetics
A eutectic mixture of local anaesthetics (EMLA)
cream is a 5% emulsion of the base forms of
lignocaine 25 mg and prilocaine 25 mg. It is applied
topically as a cream on intact skin under an occlusive
dressing and left in place for at least 1 hour. EMLA
cream is used in both children and adults to reduce
procedural pain. Some of these procedures include
circumcision, lumbar puncture, venipuncture
and dermatological procedures such as skin graft
harvesting. e efficacy of EMLA has been shown
in minor procedures in children, postoperative
circumcision and venous ulcer debridement [33,
35, 40, 188]. Overdosage is rare, although systemic
toxicity and methaemoglobinaemia may occur
when repeated or excessive doses are used. EMLA
must not be used on mucous membranes or abraded
skin as rapid absorption across these surfaces may
result in systemic toxicity [45].
Local anaesthetic can be infiltrated locally into
the wound for pain relief postoperatively. e
pre-emptive effect of local infiltration has been
demonstrated in a meta-analysis [203]. While there
is some evidence to suggest wound infiltration may
decrease postoperative pain, especially in inguinal
hernia repair and laparoscopic cholecystectomy,
it may be ineffective in procedures involving
deeper structures such as open hysterectomy and
cholecystectomy [107, 180, 311].
Regional anaesthesia and analgesia have become
more popular with more accuracy in the location of
nerves using nerve stimulators and ultrasonography.
For shoulder surgery, current evidence shows that
continuous interscalene block of the brachial plexus
decreases opioid consumption. Continuous axillary
block and intersternoclediomastoid block have not
been compared with conventional methods, but
case series demonstrated satisfactory analgesia [157].
Continuous femoral nerve block provides improved
analgesia and mobility in knee arthroplasty.
Similar findings are demonstrated in continuous
psoas compartment block for hip arthroplasty and
continuous sciatic nerve block for foot surgery [157].
Postoperative peripheral neural analgesia has been
recommended for major joint surgery including hip
and knee replacement surgery [91, 92]. Compared
with an IV patient-controlled analgesia device,
continuous lumbar plexus block has also been
reported to improve pain relief and reduce opioid
requirement after hip arthroplasty [256].
Intra-articular injection of local anaesthetic
is commonly applied for postoperative joint
procedures. A typical adult dosage is 20 ml of 0.5%
bupivacaine. Pain relief with local anaesthetics
is moderate and the effect is short term but may
be beneficial in arthroscopic knee surgery in the
ambulatory setting [181].
Continuous epidural infusion of local anaesthetic
agents is widely used for postoperative pain control
via an epidural catheter. More details are found
later in this chapter.
Adjuvant drugs
Several drugs have been used via various routes
in acute pain management, especially in the
postoperative setting, either to improve the efficacy
of conventional analgesic drugs, to reduce their
side effects, to promote the opioid-sparing effect
or to avoid the risk of progression to a chronic
neuropathic pain condition.
Adrenaline
Intrathecal adrenaline acts on the alpha-
adrenoceptor of the spinal cord. Addition of
adrenaline to local anaesthetic and opioid mixture
spinally and epidurally results in better analgesia
[183, 198, 199]. Adrenaline’s vasocontrictive action
of decreasing systemic absorption can increase
the duration of single-injection nerve block and
decrease the blood level of local anaesthetic;
although this has not been shown with ropivacaine
[26, 293].
Alpha-2-adrenoceptor agonist
Alpha-2-adrenoceptor agonists, such as clonidine
and dexmedetomidine, act both centrally and
at the spinal level. Spinal alpha-2-adrenoceptor
agonists alter nociceptive transmission by binding
presynaptically to A-delta- and C-fibre terminals
to reduce neurotransmitter release. Clonidine also
hyperpolarises the second order neuron within the
dorsal horn postsynaptically [230]. Common side
effects are hypotension, bradycardia and sedation.
Systemically administered clonidine and
dexmedetomidine have been used in the
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Acute Pain Management 107
perioperative setting and been shown to decrease
consumption of opioids postoperatively [6, 70,
125, 211]. However, the evidence is inconsistent
for intrathecal clonidine to prolong the spinal
block of local anaesthetic and synergise with
intrathecal morphine [290], although one study
showed that intrathecal clonidine could reduce
long-term hyperalgesia postoperatively [69]. In
contrast, epidural clonidine may prolong the
analgesic effect of epidural local anaesthetics and
reduce postoperative analgesic requirement [82,
176]. Finally, adding clonidine to peripheral nerve
block can potentiate and prolong the nerve block
of local anaesthetic [25, 82, 189].
Anticonvulsants
Anticonvulsants have long been used in the
treatment of chronic neuropathic pain for their
action in decreasing central sensitisation. Recently,
gabapentin has also been used in the acute setting
and is shown to be effective in postoperative pain
management [65]. Recent meta-analysis showed
that perioperative gabapentin is effective in reducing
pain scores and analgesic consumption in the first
24 hours after surgery; it works through a different
mechanism from conventional analgesics and may
be a useful addition to a multimodal analgesic
treatment regimen [120, 248].
Midazolam
Midazolam acts on the gamma aminobutyric acid
(GABA) receptor, which may play an important role
in regulating dorsal horn excitability. Intrathecal
midazolam may prolong the effects of intrathecal
local anaesthetics and decrease postoperative
analgesic requirement [230]. In terms of safety,
so far there is no indication of neurotoxicity
with intrathecal midazolam [277, 310]. Adding
midazolam with epidural local anaesthetic can also
improve analgesia [200].
Neostigmine
Intrathecal administration of neostigmine inhibits
the breakdown of acetylcholine, which has an
intrinsic analgesic property. Intrathecal neostigmine
combined with intrathecal local anaesthetic or
morphine may prolong the analgesic effect and
reduce postoperative analgesic requirement [156,
290]. However, nausea and vomiting are common
side effects and limit its use. e combination of
epidural neostigmine and opioid can also decrease
the dose of epidural opioids [290]. Neostigmine
has also been added to peripheral nerve block but
the evidence for efficacy is still lacking [189].
N-methyl D-aspartic acid antagonist
By blocking the NMDA receptors, which are
present both peripherally and centrally, one can
suppress the augmentation of the propagation of
the pain signal as well as the development of neural
plasticity. Ketamine and dextromethorphan are
the two NMDA antagonists used clinically. ere
is evidence that NMDA antagonists exhibit pre-
emptive and preventive effects [167]. Postoperative
use of ketamine demonstrates an opioid-sparing
effect, although the side effects of opioids are
not reduced [270]. In addition, a low-dose
ketamine (1.25–2.5 mcg/kg/min) may minimise
psychomimetic effects such as hallucination and
vivid dreaming [278]. A recent systematic review
showed that ketamine in low (subanaesthetic) doses
is effective in reducing morphine requirements in
the first 24 hours after surgery, and reduces patient-
controlled analgesic consumption of morphine
and postoperative nausea and vomiting without
significant adverse effect [22]. At subanaesthetic
doses, ketamine exerts specific NMDA blockade
and modulates central sensitisation induced both
by the incision and tissue damage [71].
Besides being used systemically, epidural ketamine
can improve analgesia if combined with opioid-
based epidural solution (+/- local anaesthetics) with
fewer side effects [270, 290].
Patient-controlled Analgesia
Patient-controlled analgesia (PCA) enables
patients to treat their pain immediately by directly
activating a pre-programmed microprocessor-
controlled infusion device to administer a bolus of
analgesic drug. e PCA concept of self-titrating
boluses of analgesic drug to a desired level of pain
relief and tolerable side effects accommodates the
individual variation in pharmacokinetics, tolerance
and even inappropriate pain assessment or dosing
by medical and nursing staff. In addition, the sense
of being in control of their own pain relief provides
a psychological advantage to many patients with
improved patient satisfaction.
Intravenous PCA opioid can provide better
pain relief than the conventional regimen of
opioid analgesia [289]. Many opioids have been
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108 Phoon Ping CHEN, Christopher Ping Wing CHU, Edmond Kin Nam CHUNG
used in IV PCA, such as morphine, pethidine,
hydromorphone, oxycodone and fentanyl. e
efficacy in pain control is comparable among these
opioids [227, 258, 261, 306]. Remifentanil IV
PCA can also be used in controlling labour pain
with acceptable maternal side effects and minimal
effect on neonates [288].
Some commonly prescribed IV PCA regimens and
settings are described in Table 8.09. Background
infusion of opioid during the use of IV PCA does
not confer additional benefit; it has been found to
increase the total consumption of opioid and may
expose the patients to the risk of overdose [86,
209]. is reduces the inherent safety of PCA.
Despite the relative safety of IV PCA opioid
[244, 276], a number of complications relating
to its use have been reported [86, 201, 265]. e
most serious of the adverse effects have resulted
in unintentional overdose causing respiratory
depression and hypoxaemia. Several risk factors
have been associated with these complications:
elderly patients, concurrent opioid and sedative
supplements, obesity, pre-existing sleep
apnoea syndrome, hypovolaemia, renal failure,
inappropriate patient selection and incorrect use
of PCA [86]. In some patients, drug delivery
equipment problems and incorrect programming
during the use of PCA may result in inadequate
pain relief and consequent complications [49].
Patient-controlled analgesia can also be administered
via other routes. Epidural PCA (PCEA) is another
popular modality of postoperative analgesia. More
details of PCEA can be found later in this chapter.
ere are also less frequently employed PCA routes
such as subcutaneous and intranasal PCA, which
can be as effective as IV PCA [205, 268, 280, 299].
Recently, patient-controlled incisional regional
analgesia after breast surgery has been shown to be
effective and safe [232].
Intranasal PCA butorphanol and fentanyl are
available, but significant adverse effects such as
drowsiness and postoperative nausea and vomiting
have been associated with butorphanol [74, 90].
Transdermal PCA fentanyl utilises iontophoresis
technology to overcome the problem of the dermal
reservoir. Its pharmacokinetics are similar to IV
infusion. is system has been recently introduced
into the market. e advantage of a rapid onset
needle-free patient-controlled transdermal system
(PCTS) is it is convenient and is as effective as IV
PCA [286]. e PCTS delivers a bolus of 40 mcg
of fentanyl per dose with a lockout interval of 10
minutes.
Epidural Analgesia
e administration of local anaesthetics, opioids or
a combination of these drugs through an epidural
catheter provides excellent pain relief [15, 29, 295].
ese drugs act on the spinal cord to produce
analgesia. Epidural opioid is more effective when
used in combination with local anaesthetic to
produce synergistic analgesic effects and reduce the
required dose and side effects associated with either
of the drugs. Commonly, a mixture of bupivacaine
or ropivacaine and opioid (usually fentanyl or
morphine) is infused into the epidural space to
provide postoperative analgesia (Table 8.10). A
lower concentration of epidural local anaesthetic
such as ropivacaine may provide equivalent analgesia
and is less likely to cause motor block compared
with a higher concentration [158]. An algorithm
on the use of epidural analgesia for postoperative
pain is described below (Fig. 8.01).
Table 8.09 Common IV PCA opioid prescriptions
Opioid Concentration PCA bolus dosage* Lockout interval (min)
Morphine 1 mg/ml 0.5–3 mg 5–10
Pethidine 10 mg/ml 5–30 mg 5–10
Fentanyl 10 mcg/ml 10–20 mcg 5–10
Sufentanil 2 mcg/ml 2–5 mcg 5–10
* Dosage should be reduced for elderly and high-risk patients.
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Acute Pain Management 109
Figure 8.01 Algorithm for management of epidural analgesia for postoperative pain in the general surgical
ward.
Comfortable
Unrelieved
pain
Inadequate or
no level
Test for sensory level
Exclude other
causes
Exclude other
causes
Pain
Give test dose of lignocaine
2% or bupivacaine 0.25%
Pain
Epidural infusion of
A. bupivacaine + fentanyl or
B. bupivacaine + morphine
Epidural infusion of morphine
No sensory
block
Sensory block
Fentanyl 50–100
mcg if mixture B
Consider increasing
infusion rate + PCEA dose
Consider replacing epidural
or change to IV PCA
Consider increasing
infusion rate + PCEA dose
Comfortable
Continue pre-existing
infusion regimen
Comfortable
Epidural analgesia
Give bolus
dose of infusion
mixture if
mixture A or
Fentanyl 50–100
mcg if mixture B
Adequate level but
unrelieved pain
Comfortable
Unrelieved
pain
Repeat bolus
with 0.25%
bupivacaine
Patients must be monitored closely after each bolus dose for effectiveness of pain relief and potential side
effects.
Epidural analgesia
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