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118 Chapter 10
the brainstem and thalamus, then to the cerebral cortex. Of
note, A-beta nerve fibres, which are also sensory afferents,
also terminate in the dorsal horn and can inhibit the trans-
mission of the painful stimulus. This is known as “gate
control” [13] and is the mechanism of action of a transcu-
taneous electrical nerve stimulator (TENS) machine.
Perception is the conscious awareness of pain [14].
Afferent input is interpreted by a number of systems within
the brain: sensory-discriminative (somatosensory cortex),
affective motivational (reticular and limbic systems) and
cognitive-evaluative (cerebral cortex). These systems
interact to produce the experience of pain for the patient.
This is impacted upon by genetics and previous experi-
ences among other factors, giving rise to the individual
nature of pain [14].
Modulation is the body’s impact on afferent input,
with the periaqueductal grey area most important in this
process. Modulation is most commonly recognised as
descending inhibitory pathways, whereby neurotrans-
mitters such as serotonin, noradrenaline, and GABA
reduce pain perception (and also offer targets for adju-
vant analgesics). In certain situations pain can be
enhanced rather than inhibited, particularly in the case
of neuropathic pain.
Understanding this pathway, and the sites of actions of
analgesics within it (Figure 2), can help to individualise
pain management options for a patient [15].
Opioid Receptors
Opioids are commonly used medications in palliative care
and have effect at opioid receptors. Four opioid receptors
have been identified: Mu (µ), Delta, (δ), Kappa (ĸ), and
ORL-1 (opioid-receptor-like); these are also sometimes
referred to as “MOP,” “DOP,” “KOP,” and “NOP” [16].
These receptors appear throughout the body, most com-
monly in nervous tissue, but also in other areas such as the
bowel. Endogenous opioid metabolism contributes to
many physiological functions: pain, hormonal, and
immune among others [17].
All clinically important opioid analgesics act at Mu
receptors [17]. It is also Mu receptor activation that con-
tributes to most opioid-related side effects.
Table 1 Elements of pain, grouped into their total pain domain.
Physical Psychological
“Traditional” pain Anxiety/fear of worsening pain
Impact on mobility Equating “pain” with “dying”
Requirement for analgesia Equating pain relief (especially opioids) with dying
Other physical symptoms Sense of inevitability of future severe pain
Reminder of ill health/limitations/sick role
Anger, despair, and hopelessness
Social Spiritual
Inability to work Loss of sense of purpose
Loss of role as earner, practical person, or carer for another
person
Loss of role(s) and identity
Restricted social activities and contacts Change to expected life narrative or journey
Loss of income Feeling of being punished
Changes to housing to accommodate functional changes Altered relationship with/feelings about a “higher authority” in
whatever form
Table 2 Nerve fibres transmitting pain.
Nerve Fibre Type A-delta C
Myelin Sheath Yes No
Pain Characteristics Sharp, well-localised Dull, aching,
poorly localised
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Pain and Its Management 119
Pain Types and Syndromes
Pain comes in many shapes and sizes. While pain is a
personal experience it is useful to categorise it, for
academic purposes, and particularly to guide clinical
management. Though classifications can be more com-
plex, pains can generally be classified according to their
state (nociceptive/neuropathic), type (visceral/somatic)
and temporality (constant/episodic). Table 3 displays the
types of pain commonly seen in palliative care and also
offers an overview of analgesics that are likely to be useful.
Pains are sometimes seen as “opioid-responsive” and “non-
opioid responsive.” This split is not an absolute and it is
common to see pains that are partially responsive to opi-
oids; as always it is important to assess the effect in the
individual taking the medication.
Nociceptive Pain
Nociceptive pain is very common in both cancer and non-
cancer settings in palliative care. It appears in a variety of
forms dependent upon the cause.
Visceral pain is that arising from pathology of an
internal organ or tissue. It is commonly described as vague
and poorly defined, though this is an oversimplification as
the underlying cause can give rise to a number of presenta-
tions. Damage to solid organs such as the liver tend to
cause pain that is “dull” in nature and difficult to localise.
Pain may be referred due to underlying innervation (in the
case of the liver, to the right shoulder tip). Some pains,
related to more peripheral structures such as the perito-
neum, will be more easily localised. Damage to a hollow
viscus, such as the bowel, may present with colicky pain
caused by muscular spasm of the bowel wall.
Figure 2 A schema of the neuroanatomy
of pain and the sites of action of different
analgesics.
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120 Chapter 10
Somatic pain is that related to more peripheral struc-
tures such as bone. It is commonly described as “sharp”
and is generally well-localised.
Classical nociceptive pain is caused by noxious stimuli
activating nociceptors. An inflammatory pain state has
been more recently recognised. In this instance,
inflammatory mediators activate and sensitise nociceptors,
due to causes such as inflammatory disorders or infection
[18]. For this text it is reasonable to consider inflammatory
pain a branch of nociceptive pain, though recognising this
mechanism and the underlying cause is integral for best
management.
Neuropathic Pain
Neuropathic pain arises from a disease or lesion affecting
the somatosensory system – either the peripheral or
central nervous system [19]. It is also common, affecting
up to 40% patients with cancer [20]. In this setting it may
be caused by direct invasion of the cancer (such as in
brachial plexopathy), paraneoplastic syndromes, cancer
treatment (systemic anti-cancer therapies such as plati-
num-based agents, and surgery) or non-cancer related
causes. It is also prevalent in non-malignant life-limiting
illnesses such as multiple sclerosis, peripheral vascular
disease and chronic kidney disease (especially when due
to diabetes mellitus).
Though neuropathic pain is a heterogeneous entity [20],
with pain that can be constant or episodic, some classical
findings are often seen. Words that patients commonly use
include “burning,” “stinging,” and “shooting.” There may
be concomitant sensory and/or motor changes. Pain is
usually seen in the distribution of the affected nerve(s). It
is important to identify such features, to distinguish
Table 3 Types of pain, possible opioid response, and other analgesic options.
Classification/Type
of Pain
Temporal
Characteristics Example Opioid Response Co-analgesic or Other Modality
Nociceptive visceral Constant Liver capsule pain Partial Corticosteroid
Nociceptive visceral Episodic Partially obstructing
bowel tumour
Partial response but
may exacerbate
constipation
Anticholinergic
Radiation induced
cystitis
Poor response Anticholinergic
Nociceptive somatic Constant Bone metastasis Partial Nonsteroidal anti-inflammatory
drug
Paracetamol Radiotherapy
Bisphosphonates
Cutaneous metastasis Partial Topical anti-inflammatory
Neuropathic agent
Nociceptive somatic Episodic Bone pain due to
pathological fracture
or vertebral collapse
Partial but may not
cover movement-
related pain
Muscle spasm may
also be involved
Surgical stabilization Nerve block
Radiotherapy
Muscle relaxant for muscle spasm
Neuropathic Constant Chemotherapy
induced painful
peripheral neuropathy
OR
Post-herpetic
neuralgia
Partial response Tricyclic antidepressant
Antiepileptic
Neuropathic Episodic Lancinating pain due
to brachial plexopathy
Poor response Tricyclic or other antidepressant
Antiepileptic Benzodiazepine
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Pain and Its Management 121
neuropathic pain and to identify the lesion or disease caus-
ing the pain, to allow a targeted plan to be developed [21].
Neuropathic pain is often considered harder to treat
[22]. Although opioids may be useful, this is sometimes
not the case. Neuropathic analgesics and interventional
analgesia alongside non-pharmacological methods are
often required to achieve significant improvements.
Pain Temporality
Background (“constant”) pain is that present most or all of
the time. It can be defined as occurring (or would be pre-
sent without analgesia) at least 12 hours/day over the last
week [23].
Breakthrough (“episodic”) pain is that which “breaks
through” controlled background pain. It can be specifically
defined as “a transient exacerbation of pain that occurs
either spontaneously, or in relation to a specific predictable
or unpredictable trigger, despite relatively stable and ade-
quately controlled background pain.” [24] Within this def-
inition, the authors describe two forms of breakthrough
pain, spontaneous and incident [24]. Spontaneous (“idio-
pathic”) pain occurs unexpectedly, whereas incident pain
is related to specific events. Incident pain can be further
divided into volitional (precipitated by a volitional act such
as walking), non-volitional (precipitated by an act such as
coughing) and procedural (related to a therapeutic inter-
vention) [24]. Determining the type of pain is beneficial in
developing a bespoke management plan. Bear in mind that
patients can have more than one type of incident pain.
Terminology of Pain
Pain is complex, and often best managed with a multidisci-
plinary team approach. It is useful for clinicians to have a
number of descriptors that can help classify pain, to allow
accurate and succinct discussion. Some of the terms used
are discussed below, and are often features of neuropathic
pain. When in a consultation, it is usually safer (and sim-
pler) to restrict the use of descriptors to those used by the
patient to maintain a shared understanding of the patient’s
pain experience.
Allodynia
Pain due to a stimulus that does not usually provoke pain
[25]. This could be due to a variety of modalities, including
touch, heat, and pressure. The overlying skin may or may
not be damaged.
Dysaesthesia
An unpleasant abnormal sensation that can be spontaneous
or evoked [26]. Allodynia is a form of dysaesthesia, though
the unpleasant sensation need not be painful.
Hyperaesthesia
Increased sensitivity to any stimulus, for example minor
pressure being felt more severely.
Hyperalgesia
Increased pain from a stimulus that usually provokes pain
[25]. For example, a minor insult causing severe pain.
Paraesthesia
An abnormal sensation that is not unpleasant. This may be
experienced as “tingling,” “prickling,” or “itching” among
other feelings.
Pain Assessment
Excellent pain assessment is the cornerstone of pain
management. Getting this right will allow the clinician to
best support the patient through their symptoms.
Conversely, inadequate pain assessment and a lack of doc-
umentation are thought to be the greatest barriers to good
pain relief [27]. A structured approach to assessment is
advised, and some key points need to be remembered:
• Number: Patients often have more than one pain [28]. A
rule of thumb is that a third of patients have one pain, 1/3
have two pains, and 1/3 have three or more pains.
•
Causes: In those with cancer, also consider other causes
of pain. A study found that in those with pain and cancer,
17% of pains were due to antineoplastic treatment, and
10% were due to aetiologies unrelated to cancer [29].
•
Impact: The effect of pain on functionality is sometimes
overlooked. It is important to establish this to allow
development of a multidisciplinary plan.
• Re-assess: It is essential to re-assess pain, to ensure the
correct pain mechanism has been identified, and the effect
of management strategies is evaluated.
Assessment should begin as soon as the patient is seen,
considering their appearance, behaviour, and gait. History
taking is crucial, and using a systematic approach to define
the pain such as the mnemonic SOCRATES (Box 2),
adapted to the patient, is recommended [30].
Assessment tools can be used alongside history taking to
form a picture of what the patient is experiencing.
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122 Chapter 10
Unfortunately no universally accepted tool exists [31]. The
Expert Working Group of the European Association for
Palliative Care have previously recommended using multi-
dimensional tools like the Brief Pain Inventory (BPI-sf)
and the Short Form McGill Pain Questionnaire for pain
assessment in PC (SF-MPQ) [32]. However, clinical
assessment is the gold standard [33], and it is often
pragmatic to use history taking in the first instance, adding
the use of a pain tool when pain assessment is more chal-
lenging. Tools can be useful in assessing pain in those with
significant cognitive impairment, such as dementia. The
PAINAD (Pain Assessment in Advanced Dementia scale)
and DisDAT (Disability Distress Assessment Tool) have
been shown to be effective in assessing nursing home resi-
dents with advanced dementia [34]. When using these it is
important to try to distinguish distress and pain to ensure
appropriate management. The LANSS (Leeds Assessment
of Neuropathic Symptoms and Signs) can be used in sus-
pected neuropathic pain [33].
Alongside pain characteristics, it is essential to ask about
the effect of the pain on the patient’s life and their goals for
the future. Similarly, establish the patient’s ideas about the
cause of pain, their concerns and their expectations to
further develop shared understanding. It is important to
cover co-symptoms, such as bowel function if the patient is
taking opioids. Physical examination, such as checking
sensory function in suspected neuropathic pain, is
valuable. Reviewing old investigations, to for example look
for anatomical causes of pain, and considering new inves-
tigations is also vital.
The information gained through this process should be
used to work out the type(s) of pain the patient is experi-
encing, and ultimately the mechanism(s) of the pain, which
is important in developing a targeted management plan.
Finally, patients’ underlying illnesses or co-morbidities
need to be considered. Chronic pain in the context of no
life-limiting illnesses (managed in primary care with
referral to pain clinics rather than palliative care) requires
a different approach to pain due to advanced cancer,
though holistic assessment and a personalised management
plan are needed in both cases. It is therefore important to
consider prognosis alongside the potential long-term side
effects of treatment when devising a plan.
Management of Pain
General Principles
Following assessment, a holistic management plan should
be developed alongside the patient, using the approach in
Box 4.
Box 2: History taking in pain assessment –
Using SOCRATES
• Site – Define where the pain is, checking on this for each
different pain.
• Onset – When did the pain start, and when did it pro-
gress?
• Character – A description of what the pain feels like; this
is particularly important in defining the type of pain.
• Radiation – Where the pain spreads to, which can be
helpful in defining an anatomical cause.
• Associated factors – Are there co-existent symptoms or
other features of note?
• Timing – Is the pain worse at a particular time of day?
• Exacerbating/relieving factors – Factors which make the
pain better or worse; it is helpful to know these for defin-
ing a cause but also developing a management plan.
• Severity – A description of “how bad” the pain is. Tools
such as a visual analogue scale (VAS) and numerical rat-
ing scale (NRS) can be useful to use.
Box 3: Case study
“Mr. Talbot has come to the clinic. You have taken a full
history as well as examined his abdomen and peripheral
nerves. You have also reviewed his most recent scan results.
You clearly explain that he likely has liver capsular pain as a
result of liver metastases, and neuropathic pain in the leg due
to spinal root compression from bone metastases. You con-
sider referral for palliative radiotherapy to the spine as well
as adjuvant analgesics, and help Mr. Talbot to start to develop
some goals for the future.”
Box 4: Principles of pain management
• Complete the pain assessment and discuss this with the
patient
• Consider managing the underlying cause of pain
• Support the patient to manage their pain and set realistic
goals
• Utilise the multidisciplinary team
• Use pharmacological approaches to modify pain percep-
tion
• Consider interventional approaches to interrupt pain
pathways
• Make a follow up plan
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Pain and Its Management 123
Complete Pain Assessment and Discuss This
A thorough assessment will have allowed the type of pain
to be identified and a cause for the patient’s pain(s) to be
found. Talking this through will help to support the
patient’s understanding of the situation, which will in turn
support discussion of pain management options, and sub-
sequently compliance.
Consider Managing the Underlying Cause of Pain
If there is effective treatment available for the underlying
cause of pain then this should be considered, weighing up
the benefits and burdens with the patient. For example,
this may include palliative radiotherapy in a patient with
painful bone metastases such as in Mr. Talbot’s case (Box
3), or surgical fixation where there is an impending frac-
ture due to a lytic lesion in a bone.
Support the Patient
It is important to remember the concept of total pain, and
the impacts each element can have. For example, if the
patient is struggling with anxiety or depression, pain
management is less likely to be effective, and so supporting
this with pharmacological and non-pharmacological
approaches will also help pain control.
As part of this element, it is also imperative to discuss
reasonable expectations for management of the pain, and
set realistic goals for the patient to work towards. For in-
stance, removing a pain entirely may be very difficult, but
improving it enough to allow a short car journey to the
beach may be possible.
Utilise the Multidisciplinary Team
The multidisciplinary team brings many skills that can help a
patient struggling with pain. If pain is exacerbated by
movement, a physiotherapist may be able to support a patient’s
mobility, and an occupational therapist could modify the
home environment to support this. If pain is impacted upon
by spiritual challenges, a member of the pastoral care or chap-
laincy team could support the patient to work through these.
Modify Pain Perception
Utilising medication is a cornerstone of pain management.
Many types of analgesic are available and are discussed in
the remainder of this chapter. Further approaches include
complementary therapies (discussed in Chapter 24: Patient/
Individual and Carer Wellbeing) and a TENS machine.
Interrupt Pain Pathways
Pain interventions can be neuraxial (epidural or intra-
thecal analgesia) or neurolytic (nerve blocks) and are
usually carried out by anaesthetists. They are particularly
useful for pain that has proved more resistant to analgesia,
or where there are intolerable side effects to a number of
medications. It is important to consider them early enough
for the patient to derive good benefit.
Make a Follow-up Plan
Whatever management plan has been made with the
patient, it is imperative to discuss how the benefit of this will
be assessed and followed up, to ensure continuity of care.
Pharmacotherapeutic Intervention
The majority of this management section focusses on
pharmacological options for pain management, and aims
to provide the reader with a structured approach to this
while also considering the patient as an individual.
There are many guidelines, local and national, avail-
able for pain management in palliative care, such as
NICE guidance “CG140: Palliative care for adults: strong
opioids for pain relief” [35]. This chapter is designed to
work alongside rather than instead of these. Furthermore,
certain texts such as the Palliative Care Formulary are
referenced in this chapter and provide greater
information on individual drugs. Product information
on each specific drug should be noted. In clinical prac-
tice, advice can also be gained from specialists such as
those working in specialist palliative care. As always, the
reader is responsible for their own practice and should
prescribe within the limits of their competence.
As an introduction to management, medications for
pain can broadly be divided into three groups: non-opi-
oids, opioids, and adjuvant drugs.
Non-opioid drugs are those with analgesic and antipy-
retic actions, with some having anti-inflammatory effects
too. Principally this group includes Paracetamol
(Acetaminophen) and non-steroidal anti-inflammatory
drugs (NSAIDs).
Opioids are medications related in structure to the natural
plant alkaloids found in opium, which is derived from the
resin of the opium poppy, Papaver somniferum [36]. Opioids
are grouped as “weak” (for “mild-moderate” pain) and
“strong” (for “moderate-severe” pain), the key distinction
being weak opioids having a ceiling dose and strong opioids
not. Table 4 lists drugs in each class. The term “opiate” is some-
times used; this refers specifically to drugs derived directly
from opium resin (morphine and codeine), whereas “opioids”
are the wider group of analgesics of related structure.
Adjuvant analgesics are medications originally used for
another indication (such as depression or epilepsy) that are
now utilised for their analgesic effect.
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124 Chapter 10
The WHO Analgesic Ladder
The ladder was originally developed in 1986 by a group of
experts, brought together by the Cancer and Palliative Care
Unit of the WHO. It comprises a three-step framework,
designed for the management of cancer pain, based around
pain intensity rather than aetiology [37].
Alongside the three pharmacological steps of non-opi-
oids, weak opioids and strong opioids alongside adjuvant
analgesics (see Figure 3 and Box 5), the ladder proposes
two more principles. Firstly, that analgesia is given by
mouth unless there is a compelling reason to utilise another
route, and secondly, that analgesia is given regularly (“by
the clock”), with breakthrough analgesia available
alongside this. Conventional use of the ladder dictates
starting at step 1 and assessing the effect of the analgesic
for at least 48 hours (though a longer period of assessment
may be required). If pain control is not significantly
improved, a second step 1 analgesic could be added (if
paracetamol has been commenced, a non-steroidal
anti-inflammatory drug (NSAID) would be reasonable,
considering contraindications), an adjuvant analgesic
could be included, or analgesia can be changed to step 2
(addition of a weak opioid). A similar approach applies
between steps 2 and 3, stepping up from weak opioids to
strong opioids when appropriate.
Individualising Pain Management and Issues with the
WHO Ladder
In Mr. Talbot’s case, opioid analgesia was “stepped up”
without adequate consideration of adjuvant analgesics and
non-pharmacological options for pain. This led to poor
pain control and side effects from opioids. This simple
example demonstrates the need for a multi-dimensional
pain assessment and an individualised management plan
developed on the back of this.
The WHO analgesic ladder has been widely lauded,
given the genuinely positive impact it has had on pain
management in patients with advanced cancer [15,38].
However, more recently, challenges with the ladder have
been identified. The first of these concerns the use of the
ladder for chronic pain. It is accepted that chronic pain,
while also multi-faceted and complex, is different from
pain in advanced cancer in that it is present over a longer
time course and is harder to predict [38]. Use of escalating
opioids gives rise to the possibility of long term side effects,
and a potentially unrealistic aim of resolving the pain,
whereas the approach of managing the pain in the context
of life as a whole is more likely to be effective.
The second limitation of the ladder is targeting anal-
gesia to pain intensity rather than the underlying cause.
Table 4 Opioids analgesics and their class.
“Weak” Opioids “Strong” Opioids
Codeine Morphine
Dihydrocodeine Diamorphine
Tramadol Oxycodone
Fentanyl
Buprenorphine
Methadone
Hydromorphone
Alfentanil
Figure 3 Visual depiction of the WHO analgesic ladder.
Box 5: Three steps in the WHO analgesic
ladder
Step 1
Paracetamol and/or NSAID+/adjuvant
Step 2
Paracetamol and/or NSAID+weak opioid± adjuvant.
Examples of weak opioids are codeine, dihydrocodeine, or
tramadol.
For breakthrough analgesia, use low-dose normal release
strong opioid, for example morphine NR 5 mg or equivalent.
Step 3
Paracetamol and/or NSAID+strong opioid± adjuvant.
A normal release strong opioid should be prescribed for
breakthrough analgesia alongside the regular strong opioid.
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Pain and Its Management 125
Table 5 Relative gastrointestinal toxicity of different NSAIDs.
Low Risk Medium Risk High Risk
Celecoxib Naproxen Piroxicam
Parecoxib Diclofenac Ketorolac
Ibuprofen Ketoprofen
Nabumetone
Opioids are very effective analgesics when used appropri-
ately and pain intensity is an important part of assessment.
However, the ladder has never been validated, and alterna-
tives to opioids, including both alternative analgesics and
non-pharmacological options, are preferable at times [15].
A multidimensional assessment will often find a number
of contributors to the pain, and managing these as part of a
whole person approach is much more likely to be
effective.
Further work has looked at the role of weak opioids
(‘step 2’). Some have suggested that step 2 be eliminated,
going straight from non-opioids to low doses of strong
opioids [39]. This approach has already been adopted in
paediatrics [40]. This approach is contingent on the avail-
ability of strong opioids, but is often reasonable where
cancer pain is challenging.
The opinion of this author is to focus on pain assessment,
and use this, working alongside the patient, to develop an
individualised management plan. It can useful to think about
the hierarchy that the WHO analgesic ladder describes, par-
ticularly in pain due to advanced cancer, but this must be
done in the context of the patient as a whole. With this in
mind, the ladder will be referred to as a guide during the rest
of this chapter, as part of an individualised approach.
Breakthrough Analgesia
Treating breakthrough pain is an important part of pain
management, as such pains can be debilitating. As
described earlier, characterising this into spontaneous or
incident pain through assessment will allow an individu-
alised approach. The analgesic prescribed for break-
through pain will also partially rely on the analgesia used
for background pain. For example, if a patient is using reg-
ular paracetamol, it is reasonable to prescribe a weak
opioid as required if the breakthrough pain sounds vis-
ceral, whereas for breakthrough bone pain, an NSAID
may be preferable.
Non-opioids
Paracetamol
Paracetamol is a synthetic analgesic and antipyretic. It
works mainly in the central nervous system (CNS),
through inhibition of cyclo-oxygenase (COX)-2 and also
through a number of other pathways; opioid, cannabinoid,
and serotoninergic descending pain inhibition [17].
Paracetamol can be given orally (tablets, soluble tablets,
liquid), rectally or by intravenous infusion. It is well toler-
ated but toxic in overdose. The “usual dose” is 1gram PO
QDS, though this should be reduced in those at risk of
hepatotoxicity. Risks factors include weight <50kg, poor
nutritional status, fasting/anorexia, older age and chronic
alcohol use [17]; in a patient with at least one of these, the
dose should be reduced to maximum 3 grams/24 hours. In
those with severe renal impairment (glomerular filtration
rate (GFR) < 30), the dose should also be reduced to
maximum 3 grams/24 hours. It is a useful analgesic but in
those where it is not effective it should be stopped, not
least as this helps to reduce tablet burden.
NSAIDs
NSAIDs are anti-inflammatory, antipyretic, and analgesic
in action. They act by inhibiting COX as part of the arachi-
donic acid cascade, ultimately reducing prostaglandin
production which leads to their clinical effects.
NSAIDs are now categorised depending on their selec-
tivity in inhibiting COX-2; those that are more selective
for COX-2 have less detrimental effect on platelet function
and therefore have less bleeding risk. This is important as
one of the main risks of NSAIDs is gastrointestinal tox-
icity, which can commonly cause bleeding. See Table 5 for
the relative impact of different NSAIDs on gastrointestinal
toxicity.
These drugs are very useful for pain management in
palliative care, though the benefits and risks need to be
carefully weighed up. The risks can sometimes be miti-
gated, for example reducing gastrointestinal bleeding risk
through picking a low risk NSAID, using “gastric-protec-
tion” (for example a PPI) and reducing other medications
contributing to gastrointestinal bleeding (anticoagulants,
aspirin, corticosteroids, selective serotonin reuptake inhib-
itors (SSRIs)). Cardiovascular risk cannot be removed but
historically Naproxen has been thought to be the “safest”
NSAID in this regard; more recent evidence suggests
Celecoxib may also be preferable to others [17]. Renal tox-
icity is difficult to reduce other than by maintaining
hydration. For more information on the adverse effects of
NSAIDs see Table 6.
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126 Chapter 10
Opioids
Weak Opioids
The medications in this class are Codeine, Dihydrocodeine,
and Tramadol. Formulations and other information about
each of these is shown in Table 7. Note that low dose
compound preparations (such as co-codamol 8/500) are
not recommenced in palliative care.
These drugs are designated as “weak” opioids as they
have a ceiling dose; that is, when this dose is reached,
there is no clinical indication to increase further. If this
point is reached, and pain persists and is thought to be
opioid-sensitive, the weak opioid should be stopped and a
strong opioid commenced (see Figure 4 and strong opi-
oids section).
In general, these drugs are thought to have a relative
potency to morphine of 1/10th, hence the suggestions in
Figure 4. Bear in mind that codeine is a pro-drug, with the
vast majority of its effect being gained from conversion to
morphine by the cytochrome enzyme CYP2D6. There is
known variation in the activity of this enzyme due to geno-
typic variations, and those who are poor metabolisers of
codeine will derive less analgesic effect [41]. This also
means that when such individuals are switched to strong
opioids, there is the risk that the initial opioid dose will be
too potent and opioid toxicity will follow. A dose reduction
of the strong opioid will be required in this situation to
obtain the balance between clinical benefit and adverse
effects.
Strong Opioids: Morphine
Morphine is usually the strong opioid of choice, given its
familiarity, availability and cost [17, 42]. There is, however,
no compelling evidence to suggest morphine is superior or
inferior to other strong opioids. There are times when
alternative strong opioids are useful, and these are dis-
cussed later. Morphine is an effective analgesic, with 70%
of patients with cancer pain having a good therapeutic out-
come [43].
Morphine mainly acts on µ-opioid receptors, both cen-
trally and peripherally. It is readily absorbed by the gut and
metabolised in the liver, mainly through the process of
glucuronidation. Liver metabolism is maintained reason-
ably well in hepatic impairment, and morphine often
remains the opioid of choice, though glucuronidation is
reduced if the prothrombin time is prolonged (which obvi-
ates more cautious dosing) [17].
Table 6 Adverse effects of NSAIDs.
System Involved Adverse Effects Notes
Gastrointestinal tract Gastro-duodenal inflammation, ulceration, bleeding,
and perforation
Pain, nausea, vomiting
Lower GI bleeding
NSAIDs differ in their gastrointestinal toxicity
(see Table 5)
Renal system Water and sodium retention, oedema
Hyperkalaemia
Antagonism of diuretics and anti-hypertensives
Acute renal failure especially if elderly, dehydrated,
and renal artery stenosis present
Risk of renal toxicity greater in those with
preceding renal impairment
Contraindicated in myeloma and renal
impairment
Cardiovascular system Increased risk of thrombotic events (myocardial
infarction and stroke)
Fluid retention precipitating or exacerbating
congestive cardiac failure
Contraindicated in severe heart failure
Minimise risk by using lowest dose for shortest
time
Respiratory system Bronchospasm
Exacerbation of known asthma
Rhinitis
Contraindicated if known previous sensitivity
Avoid if known severe asthma, chronic rhinitis,
nasal polyps
Use cautiously under close supervision in
asthmatic patients aged>40 years
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Pain and Its Management 127
The main metabolites of morphine are morphine-
3-glucoronide (M3G) and morphine 6-glucoronide
(M6G). Clinical effects, both analgesic but also adverse,
can mainly be attributed to M6G. These metabolites are
excreted by the kidney, and in renal impairment they
can build up, precipitating opioid toxicity. For this
reason, an alternative strong opioid to morphine
is often chosen when there is significant renal
impairment.
Initiating and Titrating Morphine
There are limited studies around the initiation of strong
opioids. A systematic review found evidence for initia-
tion with both immediate release (IR) and modified
release (MR) morphine, with neither approach being
superior [44].
The immediate release approach, with patients taking
opioids every four hours, has historically been used. This
was not based upon evidence, but upon pharmacological
considerations given that immediate release morphine has
a plasma half-life of 2–4 hours, and reaches a steady state
within 4–5 half lives. Practically, however, the expectation
of taking medication this regularly risks non-compliance,
and a modified release approach may be preferable.
Currently either approach is reasonable, and both are dis-
played in Figure 4. Further points to consider when
starting strong opioids are found in Box 6, and consider-
ations when titrating strong opioids are listed in Box 7.
Table 7 Weak opioids.
Drug Dose Range and Formulations Potency Relative to Morphine Notes
Codeine 30–60 mg QDS, maximum 240
mg/24 h
Tablets, oral syrup, and solution
(injection not used in palliative care)
Compound preparations with
paracetamol and aspirin exist
Codeine 30 mg ~ Morphine 3 mg
(bear in mind potential issues
with CYP2D6)
Also used to treat cough
Metabolised to morphine
Metabolites accumulate in renal
impairment
Dihydro-codeine 30–60 mg QDS, maximum 240
mg/24 h
Tablets and oral solution Modified
release tablets exist
Injection not recommended in
palliative care
Compound preparations with
paracetamol exist
Dihydrocodeine 30 mg ~
Morphine 3 mg
Similar potency to codeine when
given orally but twice as potent as
codeine when injected
Unlike codeine, dihydrocodeine is
not a pro-drug; hence, its therapeutic
effect is not limited by CYP2D6
inhibition
Causes toxicity in renal impairment
due to accumulation of metabolites
Tramadol 50–100 mg QDS (maximum 400
mg/24 h)
Modified and normal release tablets
and capsules
Normal release oro-dispersible
tablets
Injection (not recommended in
palliative care)
Compound preparations with
paracetamol exist
Trial evidence suggests 1/5th as
potent as morphine by mouth
(Tramadol 50 mg ~ Morphine 10
mg) but clinical experience
suggests 1/10th
A range of potencies have been
found with injection, in practice
used at 1/10th potency of
morphine injection
Less constipating than codeine/
dihydrocodeine but causes more
nausea/vomiting
Non-opioid properties
(noradrenaline and serotonin)
responsible for some efficacy and
adverse effects
Preferred weak opioid in renal
impairment as converted by liver to
inactive metabolites that are renally
excreted, though caution still
required
Avoid in uncontrolled epilepsy
Adds to risk of serotonin syndrome
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