Download Pain control in cancer: recent findings and trends

symposium article
Annals of Oncology 18 (Supplement 9): ix37–ix42, 2007
doi:10.1093/annonc/mdm292
Pain control in cancer: recent findings and trends
D. Schrijvers
Department Hematology–Oncology, Ziekenhuisnetwerk Antwerpen-Middelheim, Antwerp, Belgium
Pain is an important symptom in cancer patients. 30–40% of
patients present this symptom at diagnosis, 40–70% during
treatment and 70–90% during the palliative care phase. The
prevalence of pain depends on tumour type and varies from 5%
in patients with leukaemia to 52% in patients with lung cancer.
The cause of pain may be the tumour itself (77–80%) [bone
invasion, compression of the spinal cord or neural structures,
pressure on hollow organs (visceral pain)]; anti-cancer
treatment (15–25%) [e.g. surgery (amputation, thoracotomy,
mastectomy) chemotherapy (neuropathy), radiation
(plexopathy, myelopathy), radiotherapy-induced nerve
tumours or paraneoplastic syndromes]; non-cancer-related
pain (3–5%) or; the origin may be unknown.
Since the 1980s, the guidelines of pain treatment according to
the World Health Organization (WHO) state that analgesics
should be readily accessible, should be given ‘‘by the clock’’ on
a regular basis; ‘‘by the ladder’’ according to the intensity of
pain while the analgesic potency is sequentially escalated if pain
intensifies; ‘‘by the mouth’’; and adapted to the individual
patient. Appropriate medication for breakthrough pain should
be given; additional medication for prevention and treatment
of side effects should be provided; and careful and regular
monitoring is essential. This approach enables pain control in
80% of cancer patients.
Paracetamol and non-steroidal anti-inflammatory drugs
(NSAID) are the standard drugs of the first step of the WHO
pain ladder. Paracetamol is the simplest and safest analgesic; its
mechanism of action is not fully understood; it has a central
effect and is effective in (chemotherapy-induced) neuropathy.
NSAIDs form a very diverse group of medication. Their
principle mechanism of action is the reduction of prostaglandin
synthesis. Their indication is malignant bone pain. They have
a ceiling analgesic effect and an opioid dose-sparing effect.
Weak opioids constitute the second step of the WHO pain
ladder. Codeine is the standard weak opioid and can be used in
combination with paracetamol. Tramadol has a weak opioid
activity but influences also the noradrenaline and serotonin
re-uptake. Buprenorphine has no ceiling effect for analgesia
although it has a ceiling for side effects. It gives no restrictions
for future opioid use and has an additive effect when
co-administered with morphine.
Strong opioids are classified at the highest step of the
analgesic ladder. Morphine is still the standard drug. Other
drugs are hydromorphone (5· more potent than morphine);
ª 2007 European Society for Medical Oncology
fentanyl (100· morphine; high lipid solubility); oxycodone
(interfering with the j-opioid receptor); and methadone
[racemic mix of an N-methyl-D-aspartate (NMDA)-antagonist
and a l-receptor agonist with a half-life from up to 190 h and
a steady state after 6–12 h]. It is possible to rotate among these
strong opioids in case of side effects or insufficient activity [1].
Adjuvant or co-analgesic drugs are administered together
with analgesic drugs for specific indications (Table 1) to
improve pain control, and decrease opioid dosing and side
effects [1].
pathophysiology of pain
Pain is classified as nociceptive pain, linked to activation of
pain receptors, and neuropathic pain, due to damage of
nerve tissue [2]. It was thought to be a stable system with no
changes in the structural nerve network. New insights show
that pain perception is a dynamic system, and that structural
changes in the neural network may contribute to pain
perception [2].
nociceptive pain
The nociceptive pathway is activated by specific receptors
(Table 2) via stimulation of specialized free nerve endings in
the skin, muscle and visceral tissues by chemical, mechanical
and/or thermal stimuli. This signal is transmitted by primary
nociceptive afferents: type I and II A-delta fibres, that are
small (1–5 lm in diameter) myelinated, rapidly conducting
(5–30 m/s) neurons correlated with the initial sensation of
sharp, localized and subjectively punctuate pain or C-fibres,
that constitute the majority of cutaneous nociceptive
innervation and are small (0.25–1.5 lm in diameter),
unmyelinated afferents with slower conductance (0.5–2 m/s)
and larger receptive fields than A-delta fibres giving rise to
a poorly-localized burning, gnawing sensation.
The primary afferent sensory neurons enter the spinal cord
and synapse with neurons in the dorsal horn in the superficial
layers of laminae: the A-delta neurons synapse in laminae I,
II and V, and the C fibres in laminae I and II. A variety of
neurotransmitters are released by the primary afferent sensory
neurons: substance P, calcitonin gene-related peptide (CGRP),
and excitatory amino acids (EAAs) such as aspartate and
glutamate. Glutamate is the principal excitatory transmitter
at the synapse and binds initially to the alpha-amino-3hydroxy-5-methyl-isoxazole-4 propionic acid (AMPA)
symposium
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introduction
symposium article
Table 1. Adjuvant drugs used in pain control
Medication
Antidepressants
Amitriptyline
Anticonvulsants
Carbamazepine
Gabapentin
Neuroleptics
Haloperidol
Benzodiazepines
Diazepam
Midazolam
Anti-histaminics
Diphenhydramine
Psychostimulants
Methylphenidate
Indication
Annals of Oncology
Table 2. Specific receptors, stimuli and effect(s)
Daily oral
dosing schedule
Neuropathic pain
10–25 mg q 8 h
Neuropathic pain
Neuropathic pain
200 mg q 12 h
300 mg q 24–8 h
Nausea, delirium,
pychosis, agitation
2–5 mg q 8 h
Anxiety, muscle
spasm myoclonus
Invasive procedures
2–10 mg q 6–8 h
0.3–0.5 mg/kg (SC)
Pruritus, nausea
25–50 mg q 4–6 h
Somnolence
5–15 mg q 8–12 h
Receptor
Stimuli
Effect
TRPV1
H+
Na+, Ca2+ channel
activation
Na+, Ca2+ channel
activation
TRPV2
ASIC
CMR1
Prostanoid receptor
Aspecific activation
Serotonin (5-HT)
receptor
Noxious heat
(>45C)
Capsaicin
Noxious heat
(>53C)
Protons
Noxious cold
(8–25C)
Menthol
progostaglandin
E2
Mechanical distortion
Serotonin
kg, kilogram; mg, milligram; q, every; h, hours; SC, subcutaneously
receptor. This induces a ligand-gated Na+ current to produce
rapid depolarization. Sustained Na+ flux activates the NMDA
receptor to develop a high affinity for glutamate. Activation of
AMPA, NMDA and other receptors alters the sensitivity of
these receptors and affects their shuttling to active zones on the
neural membrane. Prolonged activation of newly synthesized
glutamate receptors can affect genomic elements to produce
durable change in the neuronal microstructure leading to
plasticity and long-term potentiation of nociceptive circuits
and long-term depression of pain modulating circuitry [2].
The second-order neurons are classified as wide dynamic
range (WDR) and nociceptive specific (NS) neurons that
spatially and temporally transform the afferent input. A small
percentage of the axons from these neurons ascend ipsilateral in
the spinal cord, but most project contralateral to form the
spinothalamic tract(s) (STT) and ascend in the anterolateral
quadrant. WDR and NS fibre activity contribute to the spatial
and temporal qualities of pain. NS neurons can remain
sensitized following repetitive noxious input and WDR neurons
exhibit prolonged after-responses (e.g. ‘wind-up’) generated
from the extent and frequency of primary nociceptive afferent
input, thus intensifying and continuing nociceptive
transmission and sensation(s).
The anterolateral spinal pathway fibres terminate in specific
regions of the thalamus, from which neuronal relays are sent to
other central nervous system centres and the somatosensory
cortex. These higher centres are responsible for the perception
of pain and the emotional components that accompany it. The
activation of supraspinal structures is mediated by EAAs [2].
Response to a painful stimulus is regulated by interactions
between multiple regions within the brain via different
neurochemical pathways. There is evidence to support
interaction between dopaminergic and adrenergic pathways
and opioid signalling pathways in the central nervous system.
Catechol-O-methyltransferase (COMT) is one of the
enzymes that metabolizes catecholamines and is an important
ix38 | Schrijvers
AMPA receptor
Glutamate
NMDA receptor
Glutamate
Polyglutamate
mGlu receptor
Glutamate
Na+, Ca2+ channel
activation
Na+ channel activation
Na+, K+, Ca2+ channel
activation
Metabotropic activation
protein kinases
Na+, K+, Ca2+ channel
activation
Na+ channel activation
NK-1 receptor
sensitization
NO production
Na+, Ca2+ channel
activation
Activation protein
kinase C
Sensitization of trk-B
Na+, Ca2+ channel
activation
Activation protein
kinase C
Sensitization of trk-B
Na+, Ca2+ channel
activation
Activation protein
kinase C
Sensitization of trk-B
TRPV1, vanilloid receptor-1; TRPV2, vanilloid receptor-like protein; ASIC,
acid-sensitive ion channel; CMR1, cold and menthol receptor-1; AMPA, 2amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid; NMDA, N-methylD-aspartate; mGlu, G-protein-coupled glutamate; NK, neurokinine; NO,
nitrogen oxide; trkB, tyrosine kinase B.
modulator of neurotransmitters in the brain. Polymorphic
variation in the COMT gene has been shown to affect lopioid neurotransmitter responses to a pain stressor and to
influence inter-individual variation in pain sensitivity [3].
neuropathic pain
Neuropathic pain arises following nerve injury or dysfunction.
After nerve damage, an altered expression of ion channels
results in neurons becoming hyperexcitable and generating
ectopic activity, which is thought to lead to the genesis of
spontaneous and paroxysmal pain.
Peripheral nerve injury causes changes in gene transcription
and activation of various kinases and proteins, including
increased NMDA receptor activity. It also elicits hypertrophy
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and activation of glial cells, including microglia within the
grey matter of the spinal cord. Following activation, microglia
release various pronociceptive cytokines (interleukin-1, tumour
necrosis factor alpha, neurotrophins), which exacerbates
nociceptive transmission and contributes to the sensitization
and maintenance of neuropathic pain [4].
Neuropathic pain may be caused by peripheral mechanisms
such as regeneration after nerve injury or demyelination of
nerves. These processes may cause increased neuronal
excitability and are linked to an increased expression of
sodium channels.
Central mechanisms involve the spinal sensitization with
heightened sensitivity of spinal neurons, reduced activation
thresholds and enhanced responsiveness to synaptic inputs.
It is mediated by the NMDA receptor [4].
The sympathetic nervous system is also important in
neuropathic pain since sympathectomy induces pain relief.
Sympathetically maintained pain may be due to sprouting of
sympathetic neurons into dorsal root ganglia of injured sensory
neurons and post-injury sprouting of sympathetic fibres into
the dermis [4].
Several efferent pathways and ligands or drugs that
modulate pain have been described (Table 3). These include
the corticospinal tracts, which start in the motor cortex and
synapse in laminae III–IV; hypothalamic efferents, which arise
in the hypothalamus and synapse in the mid-brain, pons,
medulla and lamina I; and extensive efferent fibres from the
periaqueductal gray matter in the mid-brain and the nucleus
raphe magnus in the medulla to the dorsal horn [2].
These pathways modulate nociceptive transmission in the
periphery, in the spinal cord by altering neurotransmitter
release, or supraspinally by activation of inhibitory pathways.
Several neurotransmitters are involved in inhibition of pain
transmission: norepinephrine, serotonin and opiate-like
substances (endorphins) are present in the brainstem inhibitory
pathways that modulate pain in the spinal cord; gamma-amino
butyric acid (GABA) and glycine in the dorsal horn;
somatostatin in the dorsal root ganglion and in afferent
terminals of the dorsal horn of the spinal cord; and galanin
present in primary afferent nociceptive fibres and is thought to
be an inhibitory peptide [2].
are all pain modulating receptors
the same
Several opioid (l1 and 2; d and j) and cannabinoid receptors
(CR1 and CR2) have been identified that are activated by
endogenous ligands and are implicated in pain modulation.
l1 and 2 opioid receptors are influenced by b-endorphin 1
and 2; d receptors by enkephalin; and j receptors by
dynorphin while the cannabinoid receptors are influenced by
endogenous anandamide and 2-arachidonoylglycerol.
Opioid receptors are widely distributed in the
gastrointestinal and pulmonary tract and influence other
systems (e.g. immune system) but in pain control opioid
receptors localized in the terminal regions of primary
afferent neurons, in the dorsal horn of the spinal cord, the
medulla and in the central nervous system (e.g. caudate
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Table 3. Endogenous ligands and receptors in pain modulation
Ligand
System
Receptor
Dynorphin
Enkephalin
j-opioid receptor
l- and d-opioid receptor
Endorphin
Orphanin
GABA
Glycine
Anandamide
5-hydroxytryptamine
Intraspinal
Intraspinal
Midbrain
Midbrain
Midbrain
Intraspinal
Intraspinal
Intraspinal
Bulbospinal
Nor-epinephrine
Bulbospinal
l-opioid receptor
d-opioid receptor
GABA receptors
Glycine receptors
CB1 receptors
5-hydroxytryptamine
1b receptor
5-hydroxytryptamine
3 receptor
alpha2 receptors
putamen, nucleus accumbens, claustrum, medial habenula,
dorsal endopiriform nucleus, basolateral nucleus of the
amygdala, hypothalamus, thalamus and ventral tegmental
area) are of importance [3].
The majority of the l-receptors in the spinal cord are
found presynaptically on the afferent nociceptive terminals.
Opioids that are l and/or d agonists cause a reduced release
of neurotransmitters (substance P, glutamate) from C-fibres.
Opioids also inhibit the release of CGRP. Activated opioid
receptors block the release of neurotransmitters by inhibiting
adenylyl cyclase resulting in a fall of intracellular cyclic
adenosine monophosphate (cAMP).
The predominance of presynaptic opioid receptors on C
fibres, as opposed to A-fibre terminals, accounts for the
selective effect of spinal opioids on noxious evoked activity.
The deeper layers of the spinal cord contain relatively fewer
opioid receptors; those present are believed to be situated on
nociceptive circuitry such that they have selective inhibitory
effects. When stimulated, these postsynaptic opioid receptors
hyperpolarize the membrane of dorsal horn neurons, thereby
reducing activity in nociceptive pathways.
Cannabinoid receptors influencing transmission and
modulation of pain signals are localized in the dorsal horn
of the spinal cord, the rostral ventromedial medulla and the
periaqueductal gray [5].
Activation of the different opioid receptors not only
results in pain control but induces different side effects
(Table 4) and these are dependent on the receptors that are
influenced by the agonist: l-opioid receptor agonists give rise
to respiratory depression, constipation, development of
tolerance and physical dependence, and addiction; d receptor
activation causes autonomic and neuro-endocrine system
dysfunction and mood changes; and j-opioid receptor
agonists may cause respiratory depression.
Cannabinoid receptors are influenced by cannabinoids
(e.g. delta-9-tetrahydrocannabinol of benzopyranoperidine,
benzopyranoperidine, cannabidiol, levonantradol). At
analgesic doses they may produce side effects such as mental
disturbances, ataxia, dizziness, numbness, disorientation,
doi:10.1093/annonc/mdm292 | ix39
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Annals of Oncology
Table 4. Effects of different opioid receptors
Activity
Supraspinal analgesia
Spinal analgesia
Respiratory depression
Cardiovascular
depression
Hypothermia
Diuresis
Anti-diuresis
Nausea and vomiting
Constipation
Gastroparesis
Euphoria
Dysphoria
Tolerance/dependency
Convulsions/stress/shock
Table 5. Receptor and pharmacokinetics characteristics of different
opioids
Receptor
l1
l2
j
d
x
x
x
x
(x)
x
x
x
x
x
x
x
x
(x)
(x)
x
(x)
(x)
x
Opioid receptor
activation
l
j
d
Morphine
Oxycodone
Fentanyl
Methadone
Hydromorphone
Buprenorphine
Tramadol
A(1+2)
A
A(1)
A
A
a
a
a
A
a
Receptor affinity
Solubility
Low
L
High
+
a
+
+
A
a
I
H
+
+
+
+
+
+
A: High affinity; a: moderate affinity.
x
x
X
(x)
x
(x): May be associated with this receptor activation.
disconnected thoughts, slurred speech, muscle twitching,
impaired memory, dry mouth, and blurred vision and
sedation [6].
The opioid receptors are G-protein-coupled receptors
(GPCR) and their activation by opioids including morphine,
oxycodone, hydromorphone, methadone or fentanyl results
in inhibition of neuronal transmission of painful stimuli.
GPCR signalling is regulated by receptor desensitization,
endocytosis and down regulation and the intracellular protein
ß-arrestin-2 is involved at multiple sites in this process. The
rates of l-opioid receptor internalization and desensitization
differ according to the ligand and polymorphic variation of
ß-arrestin-2.
The pain controlling effect of opioids is also influenced by
changes in l-opioid receptor densities by allelic variants with
30–50% inter-individual differences in l-opioid receptor
densities; and polymorphism in the human l-opioid receptor
gene altering the binding affinities to different opioids [7].
Cannabinoid receptors are also GPCRs that are acting via
cAMP levels and ion channels but may also be intrinsically
active and possibly coupled to more than one type of G protein.
These findings show that the pain conducting system is
modulated by different receptors and that different drugs may
act differently in individual patients at the receptor level due to
differences in genetic variability.
are all opioids the same
Several different opioids are used in pain control. However, it
should be noted that not all opioids have the same
pharmacodynamic (e.g. potency in receptor activation and
binding, number and morphology of target receptors, variation
in downstream events after receptor–ligand binding) and
pharmacokinetic characteristics (e.g. drug absorption,
distribution, metabolism, elimination) (Table 5). This may
explain the inter-individual variability in opioid analgesic
response and side effects among different opioids [7].
ix40 | Schrijvers
Drug
There is no single common metabolic pathway for the
metabolism of opioids: after administration opioids are
metabolized by the liver but this may be by different enzymatic
systems: codeine and oxycodone are primarily metabolized by
the cytochrome P450 (CYP)2D6 enzyme; morphine and
hydromorphone by the uridine-diphosphoglucuronosyltransferase (UGT) system and fentanyl and
methadone by the CYP3A4 enzyme [7].
Genetic variation in enzymatic systems may influence the
effect of opioids:
Codeine metabolisation to its active metabolite morphine is
influenced by genetic variation in CYP2D6 and 7% of
Caucasians have inactivating mutations or complete deletion
of this gene.
Morphine is metabolized by UGT2B7 to morphine-3glucuronide and morphine-6-glucuronide, and genetic
polymorphism may lead to differences in pharmacokinetics.
However, polymorphism in genes controlling the metabolism
of morphine is not sufficient to explain inter-individual
variability in morphine response.
Oxycodone, fentanyl, tramadol and methadone are
metabolized by CYP enzymes CYP3A4, CYP3A5 and
CYP2D6. Multiple single nucleotide polymorphisms have
been described in the CYP3A4 gene and some of them affect
drug metabolism; CYP3A5 may show high or low activity due
to polymorphic variation resulting in a non-functional
protein (5–15% of Caucasians); and CYP2D6 may influence
response to tramadol dependent on poor or rapid
metabolisation [7].
These findings indicate that there are important interindividual differences in the activity of different opioids and
this shows the rationale of opioid rotation in pain control [8].
does opioid-resistant pain exist
Opioid-resistant pain is defined as pain that is completely
unresponsive to large doses of opioids and that is not related to
side effects. It is estimated that 20% of cancer patients do not
respond to the traditional treatment approach with opioids.
The diagnosis of opioid-resistant pain can be made if morphine
sulfate has been administered in a dosage of at least 100 mg/h
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Annals of Oncology
(or equivalent intravenous dosing of another opiate); if there
is no pain relief, as evidenced by persistently high pain ratings
and the pain persists even after the dose of medication is
doubled and the route of administration is changed (e.g. from
intravenous to epidural); and if another opioid has been tried
unsuccessfully [9].
Several pathophysiological mechanisms have been
formulated such as down regulation of the number of lreceptors, which may be observed in peripheral nerve damage
and long-term use of opioids; cholecystokinin production
which influences the control of opioid sensitivity and is present
in certain cancer syndromes; de-activation of opioid-receptors
by G protein-activated inwardly rectifying K(+) channels
(GIRK) receptor activation leading to the inhibition of the
l-receptor or opioid-induced hyperalgesia (OIH).
OIH develops due to an imbalance of initial opioid-induced
analgesia and subsequent OIH. OIH may be turned ‘off ’ by
NMDA antagonists such as dextromethorphan, ketamine or
methadone; nitric oxide synthase inhibitors; calcium channel
antagonists; orphanin (nociceptin) receptor modulators;
neurokinin antagonists; dynorphin modulators; or ultra-low
dose opioid antagonists.
Other drugs [e.g. anticonvulsants (e.g. phenytoin,
carbamazepine, barbiturates, gabapentin); antidepressants
(tricyclic antidepressant agents, selective serotonin-reuptake
inhibitors), antihistamines (e.g. diphenhydramine,
hydroxyzine), steroids (e.g. dexamethasone, prednisone),
non-steroidal anti-inflammatory agents (e.g. acetaminophen,
ibuprofen); and psychotropic neuroleptic agents (e.g.
haloperidol)] may be tried to control this opioid-resistant
pain [9].
s
Interventional treatment:
n Neurolytic blocks
Pain treatment should be decided on these factors, but the
rationale for pain treatment should be based on the
pathophysiological mechanisms. This means that an in-depth
anamnesis and clinical examination are necessary to
differentiate between the different pain types. Differentiation
between nociceptive and neuropathic pain may be by the use of
a neuropathic pain questionnaire (e.g. DN4) (Figure 1) [3, 10].
Based on anamnesis and clinical examination a treatment
algorithm may be followed (Figure 2). There have been
other schedules. Most of them have to be validated in clinical
settings.
conclusion
The use of the pain medication according to the WHO pain
ladder controls around 80% of cancer pain. However, with the
increased knowledge of the pathophysiology of pain and the
introduction of new drugs or the fine-tuning of older
medications pain treatment will become hopefully more
effective in all cancer patients.
The new drugs and schedules should however been tested in
clinical settings in order to prove their value.
new pain treatment approaches
Several factors have to be taken into account when dealing with
cancer pain:
Patient characteristics such as performance status, age, organ
function (liver, kidney function), previous experiences with
certain medication and co-medication.
Tumour involvement as cause of pain that may direct to antitumour treatments (surgery, radiotherapy, anti-cancer
drugs).
Pain characteristics:
s
Pathophysiological mechanisms:
n Nociceptive (superficial or deep somatic, visceral) or
neuropathic pain
n Opioid-resistant pain
s
Temporal relationship based on which pain is classified
as acute, chronic, or incident pain.
Treatment characteristics:
s
Drug treatment:
n Analgesics
n Adjuvant drugs
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Figure 1. Neuropathic pain (DN4) questionnaire.
doi:10.1093/annonc/mdm292 | ix41
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Annals of Oncology
Pain
characteristics
Nociceptive
Neuropathic
Mixed
Visceral
Peripheral
Deep
Anti-depressants
+
Opioids
Adjuvant analgesics
Spasmolytics
Local anesthetics
Anti-depressants
Anti-convulsants
+
opioids
Somatic
Superficial
Deep
Paracetamol
NSAID
Opioids
Anti-depressants
Anticonvulsants
Opioids
Adjuvant analgesics
Anti-convulsants
Opioids
Opioids
Figure 2. Pain treatment according to pain characteristics.
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