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340 Carina Ching Fan LI
When the underlying cause of pain is uncertain,
it is important to establish a diagnosis with
relevant investigations and appropriate referrals to
relevant specialists. However, it is not justified to
withhold pain relief treatment while waiting for the
investigation results. Symptom relief can alleviate
anxiety and promote better patient cooperation with
diagnostic procedures [16]. On the other hand, if
a clear diagnosis is still not possible after thorough
assessment, trying to chase after a diagnosis with
more investigations and repeated tests may not be
appropriate. Patients should be considered for a
multidisciplinary approach to pain management
using a biopsychosocial model of pain.
Principles of Drug Selection
and Administration
Types of pain
Many different groups of medication are employed
in pain management (see other Chapters). An
optimal individualised regimen depends heavily
on the proper selection of analgesics, adjuvant
medications and a suitable route by which to
administer them. Pharmacological treatment of
pain requires a diagnosis and an understanding of
its pathophysiological factors. e pain can be due
to inflammation, nerve compression or irritation,
tumour infiltration, vasoactivity, ischaemia or be
sympathetically maintained. It is very important
to identify all types of pain (Table 20.01) because
each type has a different response to different
analgesic groups. For example, neuropathic pain is
much less responsive to opioid analgesics. Tricyclic
antidepressants and anticonvulsants are more
effective in this type of pain.
On the other hand, acute postoperative and
traumatic pain is usually nociceptive and responds
well to opioid analgesics. Pain can also be classified
as peripheral or central in origin. Peripheral pain
originates in muscles, tendons, skeletal tissues or
in the peripheral nerves themselves. Pain can be
purely nociceptive or neuropathic, but often it is
of a mixed type in prolonged and difficult pain
conditions. Muscle spasm pain and fibromyalgia
often need a combination of different analgesics
to break the chronic pain cycle. Sometimes
sequential trials are needed to identify a useful
adjuvant. Adjuvants come from a diverse group
of drugs acting at different levels [11]. ey are
usually considered when pain is not well controlled
despite conventional analgesics such as opioids, in
neuropathic pain or other biopsychosocial pain
conditions. Please refer to other Chapters for
detailed pharmacology of these drug groups.
Pattern of pain
e pattern of pain may also influence the timing
and type of pharmacological treatment. Incident
pain is intermittent with short attacks of pain,
which may or may not be predictable. Most
somatic musculoskeletal pain is predictable and is
triggered by movement of soft tissues, muscles and
joints. Predictable incident pain is best treated with
analgesics having a fast onset and short duration of
action. Proper timing of analgesic administration
is important so that the peak of action coincides
with the discomfort elicited by a painful procedure
(e.g. wound dressing, burns dressing, radiotherapy
and physiotherapy). Analgesics can be prescribed
as pro re nata (PRN), such that they are given at
the patient’s request at appropriate intervals every
3 to 4 hours. A background analgesic may be
prescribed to avoid overshooting and euphoric
effects when administrating short- or intermediate-
acting opioids PRN. e latter can potentially lead
to confusion or pseudo-addiction, especially when
the patient exhibits craving behaviour for PRN
medication.
Persistent or continuous pain is present
throughout the day. It is best treated with longer-
acting medications, or sustained release (SR) or
continuous release (CR) formulations at regular
dosing intervals. is allows the maintenance of
a constant therapeutic drug level to treat constant
pain of a stable pattern. e goal of treatment is to
achieve effective analgesia and minimise side effects
of the long-acting medication. Any breakthrough
or incident pain can be treated with supplements
of fast-onset and shorter-acting medication given
PRN.
Table 20.01 Types of pain
• Somatic pain/nociceptive pain
• Visceral pain
• Neuropathic pain
• Psychosomatic pain
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Principles of Pharmacological Treatment 341
Nocturnal pain commonly occurs in chronic
pain conditions and has to be dealt with by
taking a higher dose of analgesic at night, or a
supplementary drug which improves sleep. Sleep
quality is very important in the overall rating of
the effectiveness of pain therapy. Sleep quality
and duration are often assessed in a patient with
pain. It is important to ensure sufficient analgesic
coverage for adequate sleep at night. If a patient’s
sleep is frequently interrupted by pain, the effect
of insomnia, irritability and other factors may
reduce the patient’s pain threshold and precipitate
the vicious cycle of chronic pain. Isolated
insomnia requires detailed screening for emotional
disorders, such as depression and anxiety, using
proper assessment tools (see Chapter 3). is may
necessitate the consultation of psychiatrists and
clinical psychologists. Analgesia is still the mainstay
of treatment if the cause of insomnia is nocturnal
pain. Adjuncts such as benzodiazepine can also be
added to improve sleep.
Breakthrough pain can be incident pain triggered
by various activities. It may occur spontaneously
(unprovoked) or by pain recurrence when the action
of the preceding dose of analgesic terminates. is
pain can be moderate to severe in intensity and is
usually controlled by an immediate release short-
acting analgesic [4]. In cancer patients with frequent
breakthrough pain which is refractory to potent
opioids at high doses, neuroaxial analgesia or other
interventional procedures may be considered [2].
Adverse eects
e risk benefit analysis of therapeutic effect versus
side effects needs careful consideration. Relieving
pain may result in gastrointestinal complications,
respiratory depression, severe nausea and emesis.
When prescribing analgesics with potentially
serious side effects, such as opioids or other central
nervous system depressants, always “start low, go
slow”. is is especially true for the longer-acting,
slow-release formulations. It is always better to
prescribe a low-dose, longer-acting preparation
with regular dosing, and supplement it with PRN
medications as rescue analgesics for breakthrough
and acute episodic painġ[7]. is allows the gradual
build up of serum levels of analgesics with different
pharmacokinetics to provide a good background
cover and overall control of pain sensitivity. Usually
it takes three to five doses to reach a plateau level
of analgesia.
Age considerations
It is well known that the assessment of pain in
very young children and old people with cognitive
Figure 20.01 Diagram to show the dosing waves of different drugs’ pharmacokinetic (PK) serum drug levels.
Dose 1
Dose 2
Dose 3
Time
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342 Carina Ching Fan LI
impairment is difficult and challenging. As a result,
pain may be under-treated in some patients from
these groups. Although it is common to prescribe
the dose of medication according to body weight
in an adult patient, this dose must be adjusted in
young children and the older persons as age-related
changes in anatomical and physiological processes
must be taken into account. ese changes may
alter the pharmacokinetic and pharmacodynamic
responses to analgesics, narrowing their therapeutic
index and increasing the risk of toxicity and drug-
drug interactions. In addition, multiple medications
taken for a variety of medical conditions in old age
also increase the risk of drug interaction. Please
refer to Chapters 18 and 19 for more details.
Pregnancy
Despite the common occurrence of pain during
pregnancy, e.g. back pain, migraine and headache,
there is still a lack of scientific evidence for the
management of pain affecting this group of patients,
apart from following the general guidelines for the
use of medications in pregnancy. Before prescribing
any medication, the physician has to consider the
drug effects for the mother and the fetus, as well as
the course of the pregnancy [17]. e gestational
age of the fetus is important in order to avoid
exposure to teratogenic drugs, particularly during
the organogenesis stage from the 4th to the 10th
week of gestation. Drug effects in later stages of
pregnancy may lead to multiple organ involvement,
developmental syndrome or intrauterine group
retardation. Some medications may not affect the
fetus directly, but may interfere with the physiology
of the pregnancy process and increase the risk of
placental bleeding. e principle of pain therapy in
pregnancy is to use a minimal amount of analgesic
and to use non-pharmacological therapy as far as
feasible. It is very important to balance the risks
and benefits of pharmacological therapy for each
individual pregnant woman.
Route of administration
e route of administration is also a very important
consideration in pain management (Table 20.02).
e oral route is the preferred route for pain
treatment whenever it is available and feasible.
It is convenient for the patient, especially in the
outpatient setting. It is also flexible and often
achieves a reliable and steady analgesic blood level.
e oral route allows patients to take the drugs
themselves and to rely less on medical attention.
Oral preparations come in several forms: tablets,
capsules or liquids. In patients with swallowing
difficulties, liquid formulations can be given via a
nasogastric or gastrostomy tube.
Some tablets can be crushed, dissolved or made into
a suspension. However, this is not to be encouraged
as a routine procedure. Some slow-release opioid
preparations are prepared in the form of a tablet
consisting of small granules of active ingredient
embedded in different thicknesses of matrix. is
allows a gradual release of the active ingredient
over a longer time-span. Such controlled-release
preparations must never be crushed to a powder
as this leads to immediate release of drug and
potentially to acute toxicity. Although by far the
most prevalent route is oral/enteral, analgesia is
sometimes not satisfactorily achieved despite dose
escalation or frequent administration. Switching to
an alternative route using the same analgesic can
result in marked improvement in analgesia. For
example, patients may not tolerate oral morphine
because of nausea/emesis or there may be a
mechanical obstruction (tumour). Switching to
parenteral morphine using the subcutaneous (SC),
intravenous (IV) or spinal route often achieves
much better analgesia. e transdermal route
shares similar advantages with the oral route and
additionally avoids the first-pass effect. A common
example is the use of a fentanyl patch in cancer
pain patients with intestinal obstruction. Caution
must be taken with this route because it may lead
to dangerous over-dosage due to a sudden surge in
serum level with skin hyperemia after a hot bath or
the local application of a warm pad.
Table 20.02 Different routes of administration of
pharmaceutical preparations
Non-parenteral
• Oral
• Transdermal
• Sublingual
• Rectal
• Transmucosal: nasal/vaginal
Parenteral
• Intravenous
• Intramuscular
• Subcutaneous
• Intrathecal
• Epidural
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Principles of Pharmacological Treatment 343
Multimodal Therapy
A multimodal analgesia regimen is a logical
approach to optimum pain management. It uses a
combination of different analgesics (with different
mechanisms of action) to achieve analgesia
through an additive or synergistic analgesic
effect. Drug combinations also reduce the dose of
individual drug required for adequate pain relief
and minimise the side effects of each drug [21]. A
multidisciplinary and multimodality approach to
pain therapy is the modern approach for effective
pain management. Pain being multidimensional in
nature requires a biopsychosocial approach in its
management. Effective application of the principles
of pharmacological treatment is an integral part of
the patient’s total pain management.
Expectation of treatment
Many patients with chronic pain tend to have
unrealistic pain relief expectation. orough
discussions about the therapeutic effects of
different options provided by pharmacological
or multidisciplinary therapy are very important
for patient understanding and compliance. is
is especially so in non-cancer patients when the
cause of pain may not be clear. e plan for the
pharmacological therapy may need to be revised
at intervals in response to changes in the patient’s
activities and integration with other therapies. It has
been shown that the therapeutic effect is importantly
related to the patient’s expectations [13]. ere are
emotional consequences and behavioural responses
to the cognitive and emotional aspects of pain
therapy [12].
ere are limitations to pharmacological therapy.
e implication of long-term drug therapy is the
inevitable accompaniment of side effects, tolerance
and addiction issues. In many instances, the analgesic
effect may not be satisfactory. Furthermore, when
significant psychological, cognitive and behavioural
issues are present, the pain may not respond to
pharmacological treatment for pain relief alone.
Multimodal analgesic therapy has to be considered
with multidisciplinary intervention.
Individualised prescription plans
All cases are unique and the simple adoption of
a fixed prescription regimen applicable to every
patient is not realistic. All successful treatment
strategies need to be individualised with respect
to a specific individual’s analgesic requirement
and tolerance to side effects. Modification of drug
selection, timing and route of administration must
be selected to achieve optimal therapeutic and
minimal adverse effects.
Drug compliance
Although a prescription may be written to
include the best drug combination and timing of
administration for an individual, it will be useless
unless the patient is compliant. e patient may
be skeptical about the drug used (e.g. potent
opioids) due to cultural beliefs, ignorance or
incorrect concepts prevalent in society (e.g. taking
potent opioids leads to addiction). is indicates
the importance of communication with patients
and their carers to ensure that prescribed drugs
are taken correctly to achieve set goals. Proper
patient education on why and how to administer
the drugs, as well as subsequent plans, will help to
balance pain expectations and tolerability to side
effects. Many patients do not understand that some
medications may need days or weeks to act and
to reach maximal desirable effects. An impatient
individual may prematurely stop an otherwise
effective slow-onset drug before its therapeutic effect
is reached. On the other hand, a patient may stop
an effective medication when the desirable effect
is reached, due to fear of tolerance and addiction.
Discussing the treatment plan with patients allows
them some sense of control and enhances better
drug compliance.
e use of long-acting preparations (hence less
frequent dosing) will improve drug compliance
through enhancing patient/carer convenience.
Most chronic pain patients take multiple
medications and it is very important to teach them
to recognise the purpose and formulation of the
different drugs for their diseases [6]. Also, it is
important to follow up a patient more frequently
when starting a new drug. Even a phone call is
desirable if a proper follow-up visit is not feasible.
In patients in whom the underlying disease
process is expected to progress, resulting in poor
pain control (e.g. cancer), the pain management
strategy will require continual evaluation and
adjustment. It is very important to teach patients
to cope with flare-ups appropriately with analgesics
and pain-coping lifestyle modifications. Non-drug
interventions such as neurolytic blocks should also
be considered.
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344 Carina Ching Fan LI
References
Benedetti F, Mayberg HS, et al. Neurobiological mechanisms of the placebo effect. J Neurosci 2005;25:10390–402.
Burton AW, Rajagopal A, Shah HN, et al. Epidural and intrathecal analgesia is effective in treating refractory cancer
pain. Pain Med 2004;5(3):239–47.
Colloca L, Benedetti F. Placebos and painkillers: Is mind as real as matter? Nat Rev Neurosci 2005;6:545–52.
Enting RH, Mucchiano C, Oldernmenger WH, et al. e “pain pen” for breakthrough cancer pain: 1 promising
treatment. J Pain Symptom Manage 2005;29(2):213–7.
Benedetti F. Placebo analgesia, nocebo hyperalgesia. Clinical Updates. Seattle: IASP Press, March 2007.
Ferrell BR. Issues in cancer pain management: Models of success. Cancer Pract 2002;10(Suppl 1).
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Pharmacological interventions should be
increased to full therapeutic and tolerated doses
before switching to a different agent. In patients
receiving an analgesic combination, the individual
components must be titrated independently. Fixed
combination analgesics may be less desirable
in complex pain cases, although they are more
convenient for the patient.
Drug interactions
Drug interactions occur when different drugs
are given concurrently. ey are not necessarily
predictable on the basis of their effects when given
alone. e net effect can be inhibitory or enhancing
of either drug. Multiple mechanisms are involved
in analgesic drug interactions. is may be due to
different chemical and physical properties, changes
in absorption, protein binding, excretion of drug
and metabolism. e gastrointestinal absorption of
one drug may be affected if the drug is taken by the
oral route. Non-steroidal anti-inflammatory drugs
(NSAIDs) are bind highly to proteins and may
displace other drugs. Drug transformations may
occur with some opioids giving rise to metabolites
which are active and have a longer half-life
compared with the parent drug.
Some drugs may increase cardiovascular events,
gastrointestinal bleeding and the risk of seizures.
Special considerations have to be taken into account
when prescribing NSAIDs, tricyclic antidepressants,
tramadol, selective serotonin release inhibitors and
other psychomimetic drugs. Most commonly, the
effects are an enhancement of analgesic activity but
also with increased respiratory depression, sedation
and convulsions. Prescriptions have to be adjusted
with consideration to patients of extreme age, with
organ failure, in terminal palliative care and with
cognitive dysfunction.
Placebo Eect
A placebo is an inert substance which is reported
to improve symptom relief, healing and recovery.
It has been reported that up to 56% of the
population may respond to treatment with a
placebo [18]. About 20–40% of active drug effects
have been attributed to a placebo effect [19].
is is a kind of body-mind interaction with a
variety of responses resulting from psychological,
biochemical and neuroanatomical mechanisms in
different populations, experimental manipulations
and contexts [1, 3]. Both conditioning and
expectancy mechanisms using simple verbal cues
are complementary and important in the placebo
response. ere have been discussions as to whether
the deceptive (intentional) use of placebo is
unethical in the clinical setting, even in research, for
pain patients [10]. An individual may have different
placebo responses depending on the context (e.g.
setting, patient-doctor relationship, interactions
and communication) in which the placebo is given
[8]. e overall effect of drug administration results
from a combination of the pharmacological action
of the drug and the psychological context in which
it is given [5].
Conclusion
Drug treatment is only one of many
multidisciplinary multimodal pain management
techniques. e use of pharmacological treatment
can always be combined with other therapies,
such as interventional procedures, psychotherapy
and other treatment modalities. It is important to
change the patient’s mindset from one of “pain-
centred” to “function-centred”.
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Principles of Pharmacological Treatment 345
Ferrell BR, Juarez G, Borneman T. Use of routine and breakthrough analgesia in home care. Oncol Nurs Forum
1999;26(10):1655–61.
Koshi EB, Short CA. Placebo theory and its implications for research and clinical practice: a review of the recent
literature. Pain Practice 2007;7:4–20.
Loeser JD, Cousins MJ. Contemporary pain management. Med J Aust 1990;153:208–12, 216.
McCaffery M, Ferrell BR. Ethical issues in the use of placebos in cancer pain management. Oncol Nurs Forum
1996;23(10), 1587–93.
Merskey H. Pharmacological approaches other than opioids in chronic non-cancer pain management. Acta Anaesthesiol
Scand 1997;41(1 Pt 2):187–90.
Merskey HM. Pain terms. Pain 1986;(Suppl 3):S215–S221.
Merskey HM, Bogduk N. Classification of Chronic Pain, 2nd edn. Seattle: IASP Press, 1994:211.
Meyer-Rosberg K, et al. Chronic pain and functionality. Eur J Pain 2001;5:379–89.
Nicholson B, Verma S et al. Comorbidities in chronic neuropathic pain. Pain Med. 2004;5(Suppl 1):S9–S27.
Oster G, Berger A, et al. e inter-relationship between pain, sleep, and anxiety/depression. Eur J Pain 2001;5:379–
89.
Pasero CL, Britt R. Pain control: Analgesic use during pregnancy. Am J Nurs 1998;98(5):75–7.
Petrovic P, Kalso E, et al. Placebo and opioid analgesia - imaging a shared neuronal network Science 2002;295:1737–
40.
Sartorius N. Praised be placebo, may its glory shine. Croat Med J 2006;47:189–90.
Schneider C, Yale SH, Larson M. Principles of pain management. Clin Med Res 2003;1(4):337–40.
Smith MT, et al. Insomnia in chronic pain patients. J Behav Med 2000;23:1–13.
Verma S, Gallagher RM. Management of anxiety in chronic pain patients. Curr Pain Headache Rep 2002;6:30–9.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
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Introduction
Since ancient times, man has prescribed, banned, feared and
craved opioids. Wars have been named after them, their praises
were sung and laws enacted to control their distribution —
before we even knew their chemistry. It was not until 1806
that the first opioid chemical was isolated from the poppy
plant extract and named morphine (after Morpheus, the
Roman god of dreams) [88]. Another breakthrough came in
1973 when the opioid receptor was found, followed by the
identification of endogenous peptides which act on those
receptors [137].
The Opioid Receptors
Opioids exert their effects predominantly by acting on
ligand specific receptors. ey belong to a subclass of the
transmembranous G-protein coupled receptors [189].
Table 21.01 summarises some of the properties of the best
characterised opioid receptors.
e opioid receptors are further subdivided according to
responses to specific ligands. For example, the mu receptor of
mice can be classified by sensitivity to the artificial antagonist
naloxonazine (mu1 being sensitive and mu2 resistant to
antagonism). Molecular biology research has identified
further subtypes according to different splicing sequences
of the morphine receptor gene. e affiliations of these
receptor subtypes are highly specific. ere is much interest
in developing agonists (or antagonists) for specific receptor
subtypes to optimise the analgesia while avoiding specific side
effects such as respiratory depression or dependence. None has
proved to be clinically superior to others yet. Opioid ligands
also bind to other receptors such as the sigma, zeta, lambda
INTRODUCTION
THE OPIOID RECEPTORS
TOLERANCE, OPIOID-INDUCED
HYPERALGESIA AND CROSS
TOLERANCE
EQUIANALGESIC DOSE
CONVERSION AND OPIOID
ROTATION
ACUTE SIDE EFFECTS
SPECIFIC SIDE EFFECTS OF LONG-
TERM PRESCRIPTION
PHARMACOKINETIC DATA
SYNOPSIS OF SELECTED OPIOIDS
PRESCRIPTION BEHAVIOUR WITH
OPIOIDS
OPIOIDS, CHRONIC PAIN AND
SUBSTANCE USE DISORDER
EXTREMES OF AGE, LABOUR AND
LACTATION
SUMMARY
REFERENCES
21
Ming Chi CHU
Opioid Analgesics
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348 Ming Chi CHU
and epsilon (σ, ζ, λ and ε) receptors, which are
poorly characterised, or differ significantly with the
classical opioid receptors.
e classical opioid receptor has been identified
at multiple sites of the central nervous system
including the laminae I, II and V of the spinal
cord, the periaqueductal gray matter and the
rostral ventromedial medulla of the brainstem.
ere is marked heterogeneity of receptor density
and distribution within the nervous system among
individuals, and even among different neurons. is
may explain the individual variations in the effects
of different opioids. Interestingly, the endogenous
opioid system may also be the site of action of
non-opioids such as NSAIDs [185]. e opioid
receptors are also responsible for the antitussive
actions of some opioids [42].
Opioid receptors are also expressed on peripheral
nerves, and peripherally administered opioids have
been used for intraoperative and postoperative
analgesia [79, 144]. Another clinical application of
peripheral opioids is the antidiarrhoeal action of the
opioid agonist loperamide in the gastrointestinal
tract. Oral opioid antagonists such as alvimopan
and N-methylnaltrexone are useful in relieving
opioid-induced constipation and postoperative
ileus (see below).
Tolerance, Opioid-induced
Hyperalgesia and Cross
Tolerance
dependence, abuse and withdrawal are covered in
the psychiatry literature and will not be discussed.
e reader is referred to other references for the
clinical diagnosis [52], genetics and biological basis
of dependence [84, 100].
Tolerance is defined as a reduction of the
pharmacological effect or increasing dose
requirement to maintain the effect upon chronic
exposure. Apart from analgesia, other actions of
opioids such as respiratory depression, sedation
Table 21.01 Classical opioid receptors
Name Actions mediated Specific Agonists *
MOP receptor
(mu for morphine)
Analgesia
Respiratory depression
Euphoria
Constipation
Synergy with delta receptor
Morphine
beta-endorphin
DOP receptor
(delta for vas deferens of mouse)
Analgesia
Anxiolysis
Tolerance to opioids
Enkephalins
KOP receptor
(kappa for ketocyclazocine)
Visceral analgesia
Dysphoria
Ketocyclazocine
Dynorphins
NOP receptor
(for nociceptin/orphanin FQ)
Unknown Nociceptin/orphanin FQ
* Non-selective agonists for mu, delta and kappa include pethidine, methadone and buprenorphine. Naloxone is a non-
selective antagonist.
(Note: There are two naming systems for the opioid receptors: the conventional Greek alphabet system and the English
alphabet system adopted by the IUPHAR Committee in 1996 [136], in which MOP stands for Mu Opioid Peptide. The medical
literature is still largely following the Greek system.)
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Opioid Analgesics 349
or nausea also exhibit tolerance. Unfortunately,
opioid-induced constipation does not exhibit
tolerance.
e biological basis for this phenomenon is probably
multifactorial. Exposure to chronic opioids may lead
to desensitisation and down-regulation of mu opioid
receptors, which are associated with acute tolerance
in animal studies [12]. e delta opioid receptor
may also be involved in the process, as it synergises
with the mu receptor during the development
of tolerance. Some non-opioid receptors are
activated upon chronic opioid exposure and may
be involved, including the N-methyl-d-aspartate
(NMDA) receptor and nitric oxide synthase.
Opioid administration may stimulate release of
endogenous neuropeptides such as dynorphin,
which may have pro-nociceptive effects [170].
Morphine-3-glucuronide, one of the metabolites of
morphine, has an anti-analgesic effect, which may
reduce the effectiveness of morphine upon chronic
exposure, either by inducing cytotoxic reactions or
by indirect activation of NMDA receptors. While
most studies have focused on the biochemical basis
of tolerance, the expression of tolerance may have a
significant behavioural element as well [166].
Another explanation for the increased need for
opioids with exposure is opioid-induced hyperalgesia,
a state of paradoxical increase in pain sensitivity
upon opioid use [5]. is is theoretically different
from tolerance as opioid-induced hyperalgesia
implies a pathological reduction in pain threshold
with opioid use. Apart from the difference in pain
sensitivity, the difference between the two is hard
to tell in both experimental and bedside settings,
as they invariably coexist and identical biochemical
pathways are involved. Interestingly, low-dose opioid
antagonist may reduce the incidence of opioid-
induced hyperalgesia and therefore may improve
the efficacy of opioids [75]. With limited clinical
data, the clinical implications remain speculative.
As opioids exert their analgesic actions predominantly
by acting on a well-defined group of receptors
one would expect significant cross tolerance.
is is, however, not compatible with the clinical
observations (see below). Multiple mechanisms
have been proposed for such incomplete cross
tolerance: pharmacokinetic differences of different
agonists, variations in selectivity of opioid receptors
for different agonists and differences in the clinical
setting of opioid administration [136, 166].
Equianalgesic Dose
Conversion and Opioid
Rotation
One of the clinical strategies in managing tolerance
is to re-apply the opioid by another route of
administration, or to switch to another opioid
altogether. is is based on the observation that
cross tolerance is incomplete. e switching
process is largely empirical, as the equianalgesic
dose information, which is often based on crossover
trials of single doses [40], has been a subject of
controversy. Recent studies demonstrated that
previous exposure to opioids, route of administration
and the direction of conversion might significantly
affect the conversion ratios (see Table 21.02) [142].
Apart from the uncertain dosage, the process of
opioid rotation requires multiple trials of careful
titration (see Table 21.03), and the outcome is
considered unpredictable [41, 67]. Complications,
such as dysphoria, worsening pain, overdose or fatal
withdrawal, have been reported [61, 122, 191].
A recent review of published data on opioid
rotation revealed that most of the data are case
reports, retrospective studies or prospective non-
controlled trials [148]. Most of the reports focused
on methadone only, and there are only very few
Table 21.02 Examples of equianalgesic dose ratios
for chronic cancer pain [30, 54, 94, 153]
Opioid Ratio Comments
Morphine to
methadone
4:1 to 12:1 Ratio increase
with dose of
previous opioid
Morphine to
hydromorphone
5:1 Ratio drop
to 4:1 when
switching from
hydromorphone to
morphine
Morphine to
oxycodone
1.5:1 Ratio reversed
to 0.7:1 when
intravenous route
is used
Morphine to
fentanyl
1:66 to
1:85
Subcutaneous
infusions or
transdermal
preparations
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