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140 Siu Lun TSUI, Chi Wai CHEUNG
as an adjunct in such circumstance. Subsequent
dosage reduction may be possible when anti-cancer
therapy starts to work. On the other hand, in cases
of non-responsive malignancies, symptomatic
management is the mainstay of therapy for the
cancer patient. Symptomatic pain management
can be categorised into systemic medications
through oral or parenteral routes, interventional
procedures, adjuvant therapy, specific treatments
like palliative cancer therapy and immobilisation
of unstable fractures.
Systemic Analgesia
e first line of cancer pain treatment is systemic
analgesics. e essential principles are outlined in
Table 9.05. Patients can usually manage well at
home with oral medications because their use is
simple, safe and avoids the need for special training.
e choice of drug is discussed in later paragraphs.
e need for individualisation and customisation
in designing an analgesic regimen cannot be over-
emphasised. e purpose of such a tailor-made drug
regimen is to provide seamless analgesia to cover
background as well as breakthrough pain. ere is
an extensive inter-individual variation in response
to opioid analgesics. e minimal effective analgesic
concentration varies 5.5-fold and 2.6-fold for
morphine and pethidine respectively [3, 30]. On
top of this, pharmacokinetic variations also affect
the availability of analgesic to its site of action. e
choice of an appropriate drug combination with
an initial titration of efficacy and side effects allows
rapid formulation of an effective regimen for an
individual. To ensure good efficacy, adequate doses
of drugs should be given at regular intervals before
the pain recurs [134]. Prescriptions involving only
a pro re nata (PRN) regimen without a regular
analgesic are not advisable, since a higher dose of
analgesic is needed after symptoms recur as a result
of pain facilitation. However, a rescue drug should
also be prescribed PRN in addition to regular
doses for any breakthrough pain, which commonly
occurs in cancer pain. Such rescue drugs must have
a rapid onset so as to minimise patient suffering.
Good quality pain control cannot be achieved
without effective control of other symptoms. It
may be difficult to ensure adequate absorption of
an oral analgesic in a patient who is also suffering
from nausea and emesis. e patient may vomit up
any ingested drug and be reluctant to take further
opioid analgesics, as the latter can cause nausea
and emesis. Fortunately, most of the side effects
of opioid analgesics, apart from constipation,
are self-limiting and transient. It is important to
monitor the patient closely for nausea, vomiting,
somnolence and constipation, especially during
the initiation of therapy. e first three side effects
can be controlled effectively with antiemetics
(metoclopramide) and a central nervous system
stimulant (methylphenidate). Use of these drugs
can usually be tailed off after 2 to 3 weeks with the
development of tolerance to side effects. Constipation
is a persistent and resistant side effect of opioid
analgesia [62]. It is our routine practice to give a
prophylactic laxative when opioid is prescribed for
cancer pain control. Laxatives of the gut stimulant
group such as bisacodyl and sennatoside B are most
useful for this purpose. A stool softener may also be
added to improve clearance of the bowel. Recently,
peripheral opioid receptor antagonist alvimopan
has been tried in the treatment of opioid-related
constipation [70]. It is important to monitor the
effectiveness of pain control, change in functions of
major organs as well as control of side effects. Since
cancer is dynamic and progressive, appearance of
new pain and tolerance to analgesics often occur.
On the other hand, deterioration in hepatic and
renal function affects drug elimination. Failure to
adjust dose appropriately results in drug overdose.
It is our practice to follow up the patient more
Table 9.05 Principles of prescribing analgesics for
cancer pain control
1. Oral route preferred
2. Customisation of drug regimen to individual
patient
3. Background analgesia, administration before
pain recurs
(a) Adequate dosage
(b) Regular administration interval, time
contingent regimen
4. Rescue analgesic for any breakthrough pain
5. Monitoring of efficacy and side effects
6. Aggressive treatment of side effects
7. Appropriate adjustment of regimen in response
to change in the patient’s clinical condition
(a) Deterioration in major organ function
(b) Drug tolerance
(c) Appearance of new pain
8. Follow the principles of the WHO analgesic
ladder.
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Cancer Pain 141
frequently towards advanced stages of malignancy
so that prompt and appropriate adjustment to the
analgesic regimen can be made.
Choice of drugs
e choice of analgesic depends on the nature
and severity of the pain. Conventional analgesics
such as non-steroidal anti-inflammatory drugs
(NSAIDs) and opioid analgesics are effective for
nocigenic pain. For neuropathic pain with burning
or shooting characteristics, tricyclic antidepressants
or membrane stabilisers respectively are the drugs
of choice. Cancer pain frequently has multi-
components so that both nocigenic and neuropathic
pain co-exist. A combination of NSAIDs, opioids
and antidepressants/anticonvulsants are often
prescribed. e WHO recommended an “analgesic
ladder” in 1986, to serve as a simple and practical
guideline in routine cancer pain control [151]. is
guideline was updated in 1996 [152]. Basically,
initial attempts to control cancer pain should
start with simple analgesics such as paracetamol
or NSAIDs, with or without adjuvants drugs (also
known as co-analgesics). In cases of inadequate
analgesia, the drug combination is stepped up to
incorporate a mild opioid analgesic like codeine or
dihydrocodeine. Potent opioids such as morphine
or methadone are prescribed in the event of more
severe pain [151]. is approach is simple, proven
to be effective and feasible in developing countries
without sophisticated health care systems [59,
119, 157]. e analgesic ladder serves only as a
guideline, the choice of drug and rate of escalation
relies on the clinician’s experience as well as
individual response. It has been reported that in
terminal cancer patients suffering from mild to
moderate pain, those given potent opioid as first
line of treatment had significantly better quality of
pain relief and less change in therapy than those
started on mild analgesics following the analgesic
ladder [77]. It would defeat the purpose of patient
care by withholding potent opioid in order to
climb up the ladder step-by-step in a patient
suffering from severe cancer pain. Moreover,
other classes of analgesics such as ketamine
are also valuable in cancer pain management.
Incorporation of different types of analgesic and
adjuvant drugs to provide an efficacious regimen
to provide multimodal analgesia should be the
modern approach.
Opioid analgesics
Opioids are the most important group of analgesics
in cancer pain management. As a general rule,
opioid analgesics are given at a sufficient dose to
relieve pain without producing intolerable side
effects. Unlike NSAIDs, opioid agonists do not
demonstrate a ceiling effect. ere is no “maximum
dose” of opioid in treating cancer pain, as long as
the side effects are tolerated. Until recently, many
medical practitioners adopted a very conservative
philosophy in prescribing opioids; while strict
control in some countries discourages the use
of opioids, even for medical purposes. Opioid
addiction, by definition, is rare — if it does exist at
all — when it is prescribed for cancer pain control
[104, 118]. Another common misconception
among clinicians is to withhold potent opioid till
the late stage of malignancy. It is important to note
that it is the pain, rather than the advancement
of malignancy, that determines the use of potent
opioids [62]. Even when the correct choice of
potent opioid is made, it is not uncommon that the
dose is inadequate and the time interval between
each administration is excessively long.
e relative potency of morphine given parenterally
to the oral preparation is about 1:6 for a single
dose and 1:3 for repeated doses [118]. Taking
intramuscular (IM) morphine sulphate 10 mg
for comparison, it is equivalent to oral morphine
(syrup) 60 mg, oral slow release morphine 30
mg, oral methadone 20 mg, oral codeine 200 mg,
pethidine 75 mg IM and transdermal fentanyl 0.1
mg [49, 54, 97]. Please also refer to Chapter 21 for
details of opioid pharmacology.
A moderately potent opioid is usually started for
cancer pain that is inadequately controlled with an
NSAID. Commonly used drugs include codeine,
dihydrocodeine, tramadol, dextropropoxyphene or
its combination with paracetamol/aspirin. Codeine
or dihydrocodeine at 30 mg at 6-hourly intervals is
usually effective for moderate cancer pain. Codeine
is also good for control of excessive cough in patients
with lung pathology. is drug however, fails in
7–10% of patients due to genetic polymorphism
of the isoenzyme cytochrome P450 2D6, such that
they are poor metabolisers of codeine to morphine
for its analgesic action [105]. On the other hand,
the analgesic activity of dihydrocodeine does
not depend on its metabolite dihydromorphine
and analgesic activity is not affected in poor
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142 Siu Lun TSUI, Chi Wai CHEUNG
metabolisers [116, 148]. Dextropropoxyphene
is given either as a preparation that contains the
single drug or in combination with aspirin or
paracetamol. Although dextropropoxyphene on its
own is commonly prescribed, it is said to be not
more potent than NSAIDs in relieving pain [24].
Tramadol hydrochloride is a synthetic analgesic
drug derivative of cyclohexanol. e mechanisms
of its analgesic action include weak mu-agonist
activities ( + enantiomer) and inhibition of
noradrenalin and 5-hydroxytryptamine reuptake
(both + and - enantiomers) [57]. Tramadol is
an analgesic of moderate potency of about one
tenth of morphine. In cancer pain management,
tramadol is considered as a step 2 drug in the
WHO analgesic ladder [56, 106]. Compared with
other opioids, the advantage of tramadol is its
lower risk for respiratory depression, lower abuse
potential, less sedation and less constipation [56,
71]. However, its efficacy may be inadequate in
severe pain.
Morphine is the commonest and most important
potent opioid prescribed for cancer pain control.
Different morphine preparations are currently
available to serve various clinical purposes (Table
9.06). Slow release morphine preparations (MS
Contin, M-eslon, Kapanol, Oramorph SR, Kadian,
Avinza) are most useful for providing background
analgesia. Since morphine has an intermediate
duration of action (T
1/2
of about 3–4 hours),
frequent administration is necessary to provide
adequate analgesic coverage. Slow release morphine
preparations consist of morphine embedded in
a series of matrices so that the drug is release at
different rates. Enteral absorption is prolonged
so that effective analgesia is provided over 8 to12
hours. erefore the patient can take the drug at 8-
to 12-hourly (Q8–12H) intervals instead of every
3 to 4 hours. Morphine syrup is rapid in onset
but has a short duration of action. It is commonly
used as a rescue analgesic for breakthrough pain,
as well as serving as an initial dose titration when
estimating the patient’s opioid requirement before
stabilising on slow release preparations.
An alternative potent opioid commonly used in
cancer pain control is methadone (Physeptone)
[80]. In addition to being a potent opioid agonist,
methadone has weak N-methyl-D-aspartate
(NMDA) antagonist action and may have some
effect in neuropathic pain [42, 114]. Methadone
has a relatively long duration of action of about 4
to 8 hours. is drug is extensively protein bound
and has a long beta half-life of 33 to 46 hours with
a cumulative effect on repeated dosing. Methadone
serves as a second line potent opioid when morphine
is not effective. e most serious toxicities are
respiratory depression and cardiac arrhythmia (QT
prolongation and torsades de pointes). Methadone
use in elderly patients must be cautious [101, 149].
By far the majority of cancer pain is adequately
controlled with oral regimens of opioid with/
without other drugs. In addition to the risk of
respiratory depression, other common side effects
and limitations of opioids are constipation, nausea,
emesis, somnolence, drug tolerance and dysphoria.
Most of these side effects are self-limiting and persist
for 1 to 2 weeks. Constipation is the most resistant
and persistent side effect of opioid administration.
Most patients need prophylactic or therapeutic
laxative treatment when opioid is prescribed. Please
refer to Chapter 21 for more details. Other opioid
analgesics for cancer pain management include
hydromorphone and oxycodone. e former drug
is about five times more potent than morphine;
the latter acts on kappa receptors instead of mu
receptors. Both opioids are shorter acting than
morphine; slow release preparations are available
for the use in cancer pain [140].
When cancer pain control is unsatisfactory despite
dose escalation or intolerable side effects develop,
opioid rotation is a common practice [140]. In
switching to another opioid, it is common to set
doses with reference to an Equianalgesic Potency
Table [73]. Although the table serves as a useful
reference, it is necessary to be careful as some data
are derived from single dose studies and incomplete
cross-tolerance present. It is prudent to start a new
opioid at a lower dosage and titrate accordingly.
is is particularly true for methadone, as some
Table 9.06 Morphine preparations
1. Oral
(a) Morphine syrup
(b) Morphine slow release preparations (MS
Contin, M-eslon, Kapanol, Oramorph SR,
Kadian, Avinza)
2. Rectal morphine
3. Parenteral preparations
(a) Morphine sulphate
(b) Morphine preservative free preparations
for spinal use.
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Cancer Pain 143
of methadone’s analgesic action involves NMDA
antagonism, in addition to it being a potent opioid
agonist. Some poorly controlled cancer pain can be
due to a neuropathic mechanism that is not well
controlled despite a high dose of morphine. e
patient may need an NMDA antagonist rather than
a high dose of mu opioid agonist. Switching to a
methadone dosage according to the Equianalgesic
Table might achieve good analgesia but also result
in overdosage of mu opioid agonist.
Non-oral routes of systemic
medication
If the oral route of drug administration is not
feasible for whatever reason, other routes must be
considered (Table 9.07) [68]. It has been estimated
that about 70% of cancer pain patients benefit
from an alternative route of opioid administration
at sometime before death. Transdermal opioid is a
useful non-invasive alternative to oral potent opioid
in cancer pain control [121]. Lipid soluble opioids
like fentanyl and buprenorphine preparations are in
current use. Transdermal fentanyl is released from
the skin patch at a relatively steady rate of 25 to 100
microgram/hour (depending on the pharmaceutical
preparation), so that a stable analgesia is achieved.
A newer technique of transdermal analgesic
administration is iontophoresis. More studies and
evaluation are needed for its clinical application.
Other systemic routes of opioid administration,
apart from oral, transdermal and parenteral,
include sublingual (oral transmucosal), nasal and
rectal. A newer potent opioid preparation is oral
transmucosal fentanyl citrate. is fast-onset drug
is useful to treat breakthrough pain [17, 108]. Nasal
preparation of opioid like butorphanol and fentanyl
can also be useful in breakthrough pain. Intranasal
fentanyl was initially developed for management
of postoperative pain. is preparation is similar
to intravenous (IV) fentanyl in onset of action
and pain relief, although the latter has a more
persistent effect [125]. A special device has also
been developed for patient-controlled intranasal
analgesia (PCINA) [124]. is may be useful
particularly for breakthrough pain or incident-
related cancer pain [158]. Rectal administration of
potent opioid such as morphine or methadone is
also a useful alternative in case of failure of the oral
routes.
Parenteral opioid injections are often prescribed
when oral analgesia fails. Intramuscular injection
is effective in breakthrough pain although the
injection itself is also painful. Intravenous injection
or infusion is particularly useful because of its rapid
rate of onset and predictability. For patients who
can operate the device, use of patient-controlled
analgesia (PCA) is very effective in cancer pain
control. A variety of portable PCA pumps are
available for ambulatory or home use, so that the
patient can be discharged home. e PCA pump can
be set with a stable background infusion plus a PCA
bolus at a suitable lockout interval for breakthrough
pain. If venous access is difficult, the subcutaneous
(SC) route is a good alternative. e SC catheter
needs to be changed only at weekly intervals [10].
For patients who are unable to operate a PCA,
continuous IV infusion of morphine or other potent
opioid can be prescribed. e initial hourly infusion
rate can be calculated by dividing the equivalent
parenteral daily dose (1/3 of oral morphine for
repeated dose [54]) by 24. An additional rescue
bolus is also prescribed for breakthrough pain. It
is particularly useful to prescribe a titration range
of infusion and rescue bolus for nursing staff to
adjust. Ward nursing staff are in the best position to
closely monitor the patient’s analgesia. It is logical
to authorise them to adjust morphine dosage
according to the adequacy of analgesia and the
patient’s vital functions (consciousness, respiration
and circulation). A sample prescription of an IV
morphine infusion regimen is given below for the
readers’ reference. Assuming the patient’s daily
oral MS Contin requirement is 180 mg, the daily
parenteral morphine requirement is about 1/3 of
oral dose [54, 133]:
• Morphine sulphate at 1 mg/ml in normal
saline
Table 9.07 Non-oral routes of opioid
administration
1. Transdermal
2. Nasal spray
3. Sublingual, oral transmucosal
4. Rectal
5. Parenteral injections
(a) Subcutaneous
(b) Intravenous
(c) Intramuscular
6. Neuraxial
(a) Intrathecal
(b) Extradural
(c) Intraventricular.
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144 Siu Lun TSUI, Chi Wai CHEUNG
• Initial IV infusion rate is set at 60 mg/24 hour
= 2.5 mg/hour
• Rescue bolus of 1 mg every 10 minutes on
patient’s request (PRN)
• Titrate infusion rate Q1H within the range
of 0 to 5 mg/hour so that the patient is
comfortable and spontaneous respiratory rate
is >10/minute.
For advanced cancers, suitable dosage adjustment
is necessary since the pre-terminal patient may be
somnolent and have major organ failure and be
unable to tolerate a high dose of opioid.
Non-steroidal anti-inammatory
drugs and paracetamol
Non-steroidal anti-inflammatory drugs (NSAIDs)
and paracetamol are useful in cancer pain
management because of their analgesic effect
(especially) in bone pain related to malignancy
[45, 81]. For mild pain, paracetamol or an NSAID
alone is often sufficient. For more severe pain,
this group of drugs can be given in addition to
opioids. e side effects of NSAIDs/paracetamol
are not the same as opioids. Administration of the
former allows a lower dosage of the latter (opioid-
sparing effect) resulting in less opioid-related side
effects. It is recommended in the WHO’s analgesic
ladder for the use of NSAIDs with other drugs in
the control of cancer pain (see above). In order
to control cancer pain effectively, it is desirable
to choose an NSAID that is potent and relatively
long acting with minimal side effects. Commonly
used NSAIDs include diclofenac, ketoprofen,
ibruprofen, sulindac and suppository preparations
of indomethacin and diclofenac (Table 9.08). e
limitations of NSAIDs are their efficacy and side
effects. Unlike opioids, NSAIDs have a ceiling
analgesic effect [45]. NSAIDs are less popular
now as their efficacy, when combine with opioid,
is not superior to a paracetamol/opioid regimen.
Paracetamol is much less ulcerogenic to the
gastrointestinal tract than NSAIDs.
Other groups of drugs for cancer
pain management
(Table 9.09)
Cancer pain is complex involving multiple
mechanisms. It is common to have nocigenic as
well as neuropathic components in a patient with
cancer pain [138]. e former pain component
responds well to opioid and NSAIDs; neuropathic
components require other groups of drugs
for effective analgesia. For clinical features of
neuropathic pain, please refer to Chapter 23 for
details. Tricyclic antidepressants (TCAs) [110]
and anticonvulsants are effective in controlling
neuropathic pain [9]. e analgesic effect of TCAs
is independent of their antidepressant effect and
the dose range for the former effect is also lower
than the latter. e commonest prescribed TCA for
treatment of neuropathic pain is amitriptyline [9].
Apart from its analgesic properties, amitriptyline
causes sedation, which may be helpful for the
cancer patient who is also an insomniac. However,
caution against urinary retention must be taken in
elderly male patients.
Anticonvulsants [82] and local anaesthetics [66]
are useful for the spasmodic, shooting type of
neuropathic pain. Anticonvulsants exert their
analgesic effect mainly through modulation of
voltage-gated sodium channels, calcium channels
or by enhancing the gamma aminobutyric acid
(GABA), inhibitory system [43]. e anticonvulsant
carbamazepine (Tegretol) is commonly used for
trigeminal neuralgia and neuropathic pain [111,
129]. Gabapentin is a structural analogue of
GABA, initially introduced as an anticonvulsant in
1994. Its analgesic effect was soon discovered and
this drug is gaining popularity in pain medicine
due to its good analgesic efficacy, tolerability, and
relatively fewer side effects and drug interactions.
e mechanism of its analgesic action is likely to
be an inhibitory effect on presynaptic calcium
influx through inhibition on voltage-gated calcium
channels containing alpha-2-delta-1 subunit [120].
Clinically, gabapentin is particularly effective
Table 9.08 Common NSAIDs/paracetamol
prescriptions for cancer pain control
Ketoprofen SR 100 mg qd to q12h
Diclofenac SR 100 mg qd to q12h
Sulindac 100–200 mg q12h
Indomethacin
suppository
100 mg q12h
Naproxen 250–500 mg q12h
Paracetamol 500–1000 mg q6h
Note: dose adjustment is essential especially in the elderly
or patients with impaired hepatic or renal functions.
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Cancer Pain 145
in treating neuropathic pain with allodynia,
spontaneous, paroxysmal, lancinating and steady-
burning characteristics [76]. Its effectiveness in
treating neuropathic pain related to cancer has
been substantiated [14, 113]. Pregabalin is a newer
member of this group of analgesics. Its onset of
action is much faster than gabapentin. Gamma
aminobutyric acid agonists like benzodiazepines
are also very useful in cancer pain management.
is group of drugs can be used as sedative and
hypnotics as the patient is likely to be suffering
sleep loss due to pain. Diazepam, lorazepam and
midazolam are commonly used benzodiazepines
for patients with cancer pain. In addition, drugs
like baclofen (GABA
b
) are particularly useful for
treating pain due to muscle spasm [147].
Ketamine is an NMDA antagonist which is useful
in pain resistant to morphine, especially with a
neuropathic element [130]. Ketamine can be given
IV at 0.1 to 0.5 mg/kg and used as an adjunct to
opioid therapy. Other routes of ketamine are by
subcutaneous, oral, extradural and intrathecal
administration. However, ketamine is also
associated with significant side effects including
nausea, sedation, dry mouth and hallucination
[85].
Bisphosphonates are useful in the treatment of pain
related to bone metastases. is group of drugs is
particularly effective in those malignancies associated
with marked osteolysis such as multiple myeloma
and metastatic breast cancer. Bisphosphonates act
by exerting an inhibitory action on osteoclastic
activity on bone. is activitity is stimulated by
factors secreted by malignant cells and is believed to
cause pain. Bisphosphonates are commonly given
to control bone pain, lower elevated plasma calcium
and delay pathological fractures due to malignancy
[150]. Generally, this group of drugs is safe; the
most important side effect is the rapid lowering of
calcium when the drug is administered rapidly in
patients with widespread osteoclastic activity. e
American Society of Clinical Oncology (ASCO)
clinical practice guidelines recommend a regimen
for treatment of bone pain due to metastatic
tumour: disodium pamidronate (Aredia), a second
generation bisphosphonate, 90 mg can be infused
intravenously over 2 hours, repeated every 3 to 4
weeks [4]. ird generation bisphosphonates like
zoledronic acid are more potent and can be infused
in a much shorter time than pamidronate [112].
e ASCO guidelines recommend intravenous
infusion of zoledronic acid 4 mg over 15 minutes,
repeated every 3 to 4 weeks, for malignant bone
pain [4].
Importance of analgesic
coverage when switching from
one regimen to another
In cases of unsatisfactory analgesia or other reasons
requiring a change to the analgesic regimen, it is
essential to provide adequate coverage during the
switching-over period. One method is to prescribe
a transdermal fentanyl patch to the patient whose
pain is not well controlled with oral morphine.
Fentanyl needs at least 8 hours to achieve a
sufficient plasma level [91]. Time is required for
the release of drug from the patch preparation, the
formation of a skin depot, subsequent absorption
into the blood and access to opioid receptors. If the
oral morphine is withdrawn abruptly, there may
be a period of insufficient opioid coverage when
the patient will suffer greater pain or even opioid
withdrawal symptoms. It is important to either
Table 9.09 Other useful drugs for cancer pain
control
1. Tricyclic antidepressants
(a) amitriptyline
(b) nortriptyline
(c) doxepin
2. Membrane stabilisers
(a) Anticonvulsants
• carbamazepine
• valproic acid
• gabapentin
• pregabalin
(b) Sodium channel blockers
• lignocaine
• mexiletine
3. Benzodiazepines: hypnotics, sedatives
(a) GABA
a
agonist
• diazepam
• clonazepam
(b) GABA
b
agonist
• baclofen
4. Bisphosphonates
5. Other drugs
(a) Alpha 2 agonist
• clonidine
• dexmedetermidine
(b) NMDA antagonist
• ketamine
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146 Siu Lun TSUI, Chi Wai CHEUNG
prescribe a rescue analgesic (morphine syrup or
injection) and/or tail down the old regimen drug
gradually so as to provide a smooth transition to
the new regimen.
Neuraxial Analgesia
Overview
Neuraxial analgesia is the administration of
analgesic drugs at the spinal column (intrathecal or
extradural route) or into the ventricles of the brain.
e discovery of endogenous opioid receptors in
1971 and their locations in the central nervous
system led to research and development of a new
approach to manage pain. Wang first reported the
use of intrathecal morphine on a patient suffering
from cancer pain in 1979 [143]. e neuraxial
administration of opioid and other drugs is an
important means of treating malignant as well as
non-malignant pain. e mechanism of spinal
opioid analgesia involves the administration of
opioids in the extradural or intrathecal space,
in close proximity to the endogenous opioid
receptors. ese receptors are found abundantly in
the spinal grey matter especially at the substantia
gelatinosa. Opioid agonists act on these receptors
presynaptically at the primary afferent neurons as
well as postsynaptically at the second order neurons
to inhibit pain transmission. In contrast to systemic
opioid administration, the analgesic dose ranges
of extradural and intrathecal opioids are as low as
1/10th to 1/100th respectively [84]. Spinal opioid
achieves a much better quality of analgesia and the
side effects of systemic opioid can be minimised.
Unlike neurolytic procedures, neuraxial analgesia is
reversible and produces more widespread analgesia;
it is particularly effective in cancer pain that occurs
bilaterally or at multiple sites. Please also refer
to Chapter 28 for more details on this analgesic
technique.
Extradural versus intrathecal
routes
Comparing the extradural and intrathecal routes,
the former requires a larger dose of opioid (10
times) and the onset is also delayed. With high
dosages, a significant systemic absorption may
occur and result in significant systemic side effects.
e intrathecal route is associated with a higher
success rate in pain relief [31, 52, 84]. Other
disadvantages of the extradural route include more
fibrosis around the catheter, pain on injection and
a higher incidence of catheter blockage. However,
since the drugs are deposited outside the dura
mater, the extradural route allows more flexibility
in the choice of drug.
Spinal drug delivery systems
e administration of spinal opioid alone or in
combination with local anaesthetics, α
2
adrenergic
agonists or other drugs can be achieved through
different delivery systems. e choice of the drug
delivery system depends on the life expectancy of
the patient, degree of care available to top-up the
drug and the cost.
Waldman and Coombs classified six types of
spinal drug delivery systems [142]. e type
I system involves a catheter that is inserted
traditionally without subcutaneous tunnelling.
It is simple, but has the highest risk of infection
and is only suitable for short- term use (up to 1
week). is method is commonly employed as a
temporary catheter for testing the effectiveness
of spinal analgesia before implantation of a long-
term catheter. Also, a temporary spinal catheter
allows excellent analgesia to fill the gap before
anti-cancer therapy becomes effective. e type
II system involves subcutaneous tunnelling of the
spinal catheter.
It is more resistant to spinal canal
infection and can be used for a longer period of up
to a month. is system is useful for patients with
short life expectancy and suffering from intractable
pain. A high degree of aseptic care is required to
manage type I and type II spinal catheter systems
since the injection port is exteriorised. However,
these catheters are less expensive and simpler for
insertion. Totally implantable systems, type III to
VI, are feasible for home care because their risk of
infection is much less. e type III system includes
a totally implanted subcutaneous injection port
so that drugs can be given through intermittent
percutaneous injections. Commercially available
silicon domes are resistant to multiple punctures
by atraumatic Huber needles for up to 1,000
times. In order to minimise multiple punctures, an
alternative is to administer the drug, intermittently
or by continuous infusion, though a catheter and
bacterial filter system connected to a Huber needle.
e latter is inserted percutaneously to the injection
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Cancer Pain 147
port. e needle can be changed at regular intervals
of several days to a week. Types III to IV systems
involve implanting a drug reservoir (usually with
capacity of 50 ml). is drug reservoir allows
topping-up at much longer intervals so as to further
minimise infection and trauma to the injection
port. e type IV system is a patient-controlled
system (e.g. AlgoMed System of Medtronic). In a
similar way to a PCA device, the patient presses an
implanted, manually activated pumping chamber
to deliver a 1-ml dose of drug through the catheter.
Subsequent filling of the empty chamber from the
implanted drug reservoir takes an hour, so that a
lockout interval mechanism is incorporated to
avoid inadvertent overdose. Type V and VI systems
allow continuous infusion through a totally
implanted pump to provide a constant analgesic
level at the CNS. Type VI is the most sophisticated
system in that programming of the pump is
allowed through a telemetry system. e choice
of spinal drug delivery system depends on the life
expectancy of the patient, cost affordability as well
as logistical support of the institution and patient’s
family. Generally speaking, the sophisticated totally
implantable system (IV to VI) is not feasible or cost
effective if the patient has a life expectancy of less
than three months [60, 67].
Choice of neuraxial medication
In carefully selected patients, initial good pain relief
is usually achieved with spinal opioid. Preservative-
free morphine is the commonest drug used. e
efficacy of spinal morphine is best in continuous
somatic or visceral pain. Its analgesic efficacy is less
satisfactory (in descending order) in neuropathic
pain, incident pain due to movement, visceral pain
due to intestinal obstruction and pain of open ulcer
[84]. Even with an initial good response, it is not
uncommon that analgesia becomes less satisfactory
with time. e most important causes of dose
escalation are drug tolerance, the development
of new pain as the tumour further progresses
and metastases, or mechanisms that develop as
elaborated earlier in this chapter. Metastases to the
epidural space were found in about 70% of patients
with refractory pain during intrathecal analgesia
[84].
As with systemic opioids, tolerance to spinal
opioid develops with time so that a larger dose
is needed to achieve the same degree of analgesia.
Apart from drug tolerance, it is well known that
nerve involvement is common in cancer and the
resulting neuropathic pain is less responsive to
opioid. In cases of unsatisfactory analgesia despite
rapid opioid dose escalation, other drugs should
be tried. Local anaesthetic and α
2
adrenergic
agonists like clonidine are particularly useful in
such circumstances. e addition of bupivacaine
to opioid regains analgesia in 90% of cancer
pain patients who were refractory to extradural
opioid alone [84]. Local anaesthetic is particularly
useful in substituting opioids to provide a “drug
holiday” to reset the tolerant opioid receptors,
so that a lower dose can be recommenced later.
Local anaesthetic also blocks involuntary reflexes
and spasms that aggravate pain. It has been
demonstrated that the addition of bupivacaine
to morphine in intrathecal mixtures resulted in
a diminished progression of dose escalation of
the morphine [139]. However, spinal (especially
intrathecal) administration of local anaesthetic
results in blocking touch, sympathetic as well as
motor functions. is may lead to hypotension,
urinary retention and lower limb weakness.
Extreme caution is mandatory to ensure adequate
hydration and monitoring of motor power when
local anaesthetic is used. In general, a low dose
of intrathecal local anaesthetic (bupivacaine <30–
60 mg/day) in combination with morphine and
other drugs often achieves good quality analgesia
in the absence of significant sensory impairment,
orthostatic hypotension, urinary retention or
motor weakness [84].
e alpha-2 adrenergic agonist is another useful
addition to spinal opioid in cases of inadequate
analgesia. is acts presynaptically to inhibit release
of excitatory neurotransmitters and hyperpolarise
postsynaptic neuronal membranes [146]. Clonidine
is particularly useful in case of opioid resistant
neuropathic pain complicating the malignancy
[44, 84, 136]. It is our practice to add clonidine
to morphine so that the final concentration of the
former is around 10 to 25 microgram/ml in the
mixture. Clonidine is associated with hypotension
and somnolence; extreme caution is required
when this drug is first given to a patient with
advanced cancer. Other drugs reported to be useful
adjuncts for intrathecal analgesia include ketamine,
neostigmine, lysine acetyl salicylate, baclofen,
ziconotide, adenosine and somatostatin analogues
[84, 117, 146].
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148 Siu Lun TSUI, Chi Wai CHEUNG
Neuroablative Procedures
Introduction
Neuroablative procedures are performed for pain
relief through long-term interruption of pain
pathways. is can be achieved through physical
or chemical means. e former includes heat, cold,
mechanical pressure or ablation of nociceptive
fibres through open surgery. e latter involves
application of chemical agents to cause primary or
secondary (Wallerian) degeneration of nociceptive
fibres (Table 9.10). Neuroablative procedures are
very useful for treating intractable cancer pain.
e prerequisites are appropriate selection of
patients, proper choice of procedures and the use
of modern organ imaging techniques, such as the
image intensifier or computerised tomographic
scan, which allow precise localisation of target
nerves for destruction [96]. A successful neurolytic
block usually provides good quality analgesia for a
relatively long period (3 weeks to 6 months). e
dose of potent systemic analgesics can hence be
reduced so that the side effects of these drugs can be
minimised. Although conventionally, it is common
practice to perform neuroablative procedures only
when potent opioid fails, a more modern approach
is to perform these procedures earlier. It has been
shown that neuroablative procedures performed
early in appropriately selected patients achieve
better quality of life, with reduction in both pain
and opioid consumption [35].
Common neuroablative
procedures for cancer pain
management
Localised pain such as rib metastasis can be easily
treated with neurolytic intercostal nerve block
using phenol. More diffused visceral pain can
be controlled with blockade of the nerve plexus
with an adequate volume of an appropriate
neuroablative chemical. It has been shown that
neurolytic coeliac plexus block is effective in
relieving pain due to pancreatic cancer and other
upper abdominal malignancies in 85% and 73%
respectively [102] and the dose of opioid can often
be reduced [102, 155, 156]. e first clinical series
of superior hypogastric plexus block was reported
in 1990 [99]. Published analyses showed that this
block was effective in 69–72% of patients and
opioid doses could be reduced after the block [34,
100]. Overall, neuroablation of the sympathetic
axis (coeliac plexus, superior hypogastric plexus
and ganglion impar) has been shown to be an
effective and safe approach to treat visceral pain
in cancer patients. is should be incorporated
in the armamentarium of the pain specialist as a
useful adjunct to oral pharmacological therapy
[33]. More invasive neuroablative procedures
at the CNS include intrathecal neurolysis and
percutaneous anterolateral cordotomy. Intrathecal
injection of a neurolytic agent for intractable pain
was first described in 1930 by Dogliotti [36].
Phenol and ethanol are commonly used agents
for intrathecal neuroablation. is technique is
particularly useful for pelvic and perineal pain.
However, due to the risk of incontinence and lower
limb paralysis, this procedure is seldom performed
in patients with intact urinary/bowel and motor
function. Percutaneous anterolateral cordotomy is
the destruction of spinothalamic fibres conducting
nociceptive signals of the contralateral half of the
body during their passage through the anterolateral
quadrant of spinal white matter at the cervical
level [131]. Nerve fibre radiofrequency lesioning is
conducted using a radiofrequency probe inserted at
the level of C1/2 to the appropriate target at the
spinal white matter. e placement of the probe is
guided under image intensifier control and the final
correct position is confirmed with neurostimulation.
is invasive technique is indicated for intractable
cancer pain involving one side of the body. It is
particularly effective for incident pain resulting from
unstable pathological fracture, multiple metastases,
Table 9.10 Neuroablative means for the treatment
of pain
Physical
Heat thermocoagulation,
radiofrequency
lesion
Cold cryoprobe, cold
saline
Mechanical balloon compression
Open surgery presacral
neurectomy
Chemical
Ethanol
Phenol
Others (glycerol, ammonium
sulphate)
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Cancer Pain 149
pelvic plexopathy and brachial plexopathy due
to infiltration in Pancoast syndrome. Serious
complications include respiratory failure due to
destruction of motor nerve controlling respiration
and post-cordotomy dysaesthesia. Also, reference
pain (allesthesia) may develop at the contralateral
side (mirror image of the body). is procedure
is not indicated for those with a life expectancy of
longer than 1 year. Please refer to Chapters 25, 26,
27 and 29 of this textbook for details of the various
interventional procedures.
Assessment before performing
neuroablative procedures
e choice of neuroablative procedure depends
on multiple factors as listed in Table 9.11. Before
proceeding to a neuroablative procedure, it is
mandatory to conduct a comprehensive assessment
and evaluation. Cancer pain often occurs at multiple
sites, due to local infiltration of the primary
tumour as well as at metastases. It is important to
identify all the different anatomical locations as
well as the individual pain components. Successful
interruption of pain transmission at one location
may unmask pain at other sites.
Limitations of neuroablative
procedures
e limitations of neuroablative block are
inadequate coverage due to multiple sites of
tumour involvement; new pain due to progressive
tumour infiltration and metastases; complications
of nerve destruction; and recurrence of pain after a
successful block due to nerve regeneration. It is fair
to say that neuroablative procedures complement
rather than replace systemic analgesics [96].
Psychological Management
of Cancer Pain Patients
Proper assessments of cancer pain patients’
emotional and psychological status are essential to
improve their quality of life and minimise suffering
in the final period of their life. e psychological
approach constitutes an important part of the
management plan. Management such as counselling,
education, relaxation and other techniques can be
very helpful for cancer patients with anxiety [6].
Earlier recognition of depression among cancer
pain patients is essential to reduce the death-wish.
Measurements like good patient-physician rapport
and psychological crisis intervention may reduce
the risk of suicide [47]. Studies of psychological
techniques such as cognitive behavioural therapy for
cancer pain patients [86, 127, 132] have produced
promising results and the therapy appears to be
beneficial.
Control of Other Discomforts
and Palliative Care
e WHO defined palliative care as: “e
active total care of patients whose disease is not
responsive to curative treatment. Control of pain,
or other symptoms, and of psychological, social
and spiritual problems is paramount. e goal of
palliative care is achievement of the best quality of
life for patients and their families” [152]. Although
pain is the most important symptom that requires
special management in cancer patients, other
physical symptoms and psychological sufferings are
equally distressful. Most advanced cancer patients
are suffering from 3.5 to 6 symptoms [29, 58].
Analysis of prevalence of discomforts other than
pain showed that many symptoms are common
in cancer patients, especially towards the terminal
stage (Table 9.12) [21, 26, 28, 29, 37, 58].
Active searching for, together with comprehensive
and regular assessment of, these symptoms is
Table 9.11 Assessment and evaluation before
performing neuroablative procedures
1. Anatomical location(s) of pain
(a) Primary tumour
(b) Metastases
(c) Bilateral or across the midline
(d) Multiple innervation
2. Component of individual pain location
(a) Nociceptive
(b) Neuropathic
3. Life expectancy
4. Existing disabilities versus inherent
complications of the procedure
5. Diagnostic/prognostic block and its
interpretation
6. Psychological element
7. Availability of alternative techniques
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