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350 Ming Chi CHU
trials on opioid rotation in non-cancer pain
management [64]. While there is a general trend of
improved quality after the rotation, there is a lack
of robust clinical evidence and, therefore, rotation
should be conducted with caution.
Acute Side Eects
Respiratory depression is the most feared
complication of opioid overdose. Despite its clinical
significance, there is no consensus on its definition
[97]. Respiratory responses to plasma oxygen and
carbon dioxide tension are useful in the research
setting but impractical for clinical use. Physical signs
such as desaturation and slow respiratory rate of
<10 breaths per minute are easy to use, but they do
not correlate with any biochemical or physiological
evidence of respiratory failure. Another clinical
surrogate is to monitor for sedation, which usually
precedes respiratory depression [112].
Studies on opioids used in postoperative patient-
controlled analgesia (PCA) have reported an
incidence of respiratory failure ranging from 0.5–
2.8% [13, 124]. With epidural or intrathecal opioids
for acute or cancer pain the incidence is about
0.1–1.7% [15]. Patients who are at high risk for
this adverse effect include those at extremes of ages,
with obesity and with respiratory diseases [60, 78].
It is readily reversible with naloxone, but repeated
doses may be required as the opioids may outlast
the naloxone; patients should be monitored in an
intensive care setting. Another cause of concern
is that respiratory failure represents a preventable
form of drug error as retrospective surveys have
highlighted the association between opioid side
effects and equipment errors, prescription errors
and concomitant use of sedatives [20].
Nausea and vomiting are not as dangerous but no
less bothersome in 10–61% of patients, with a
number needed to harm (NNH) of 3.6 [59, 99].
Multiple mechanisms are proposed such as direct
stimulation of the chemoreceptor trigger zone in
the medulla, enhanced vestibular sensitivity and
impaired peristalsis of the alimentary tract [118].
e risk of nausea and vomiting is also exacerbated
by the other clinical factors such as surgery,
anaesthesia and pain itself. Addition of other co-
analgesics does not seem to reduce the incidence of
this side effect even when the total dose of opioids
is reduced [149, 154].
Treatment is largely empirical and includes
central anti-dopamine agents (e.g. haloperidol,
metoclopramide), anti-serotonin agents (e.g.
ondansetron), antihistamines or anticholinergics
(e.g. diphenhydramine) and steroids. ere has
been increasing use of the anti-serotonins for
treating nausea and vomiting especially after the
US Food and Drug Administration issued the
“black box” warning against droperidol [99].
Combination therapy has been recommended for
refractory nausea [117] and for patients predisposed
to develop postoperative nausea and vomiting.
Another common side effect of opioids is pruritis,
which occurs in 2–10% of patients. With central
nervous administration of opioids the incidence
can go up to almost 100% [174]. While some
opioids may induce histamine release from mast
cells causing itchiness, the administration of opioid
antagonist naloxone can effectively reverse the
pruritis, suggesting an opioid receptor mediated
mechanism. Nonetheless, antihistamines have
been commonly used for treating opioid-induced
pruritis despite the lack of evidence of efficacy. Anti-
serotonin agents (ondansetron) are effective but
short acting, while opioid antagonists need to be
Table 21.03 Five-step approach to opioid rotation
(modified from Gammaitoni [67])
Step Task
1
Assess the patient to determine if the
uncontrolled pain is secondary to
worsening of existing pain or development
of a new type of pain.
2
Determine the total daily usage of the
current opioid, including all long-acting
and breakthrough opioid doses.
3
Decide which opioid analgesic will be used
for the new agent and consult established
conversion tables to arrive at the proper
doses. Recognise the limitations of the data.
4
Individualise the dosage based on
assessment information gathered in
Step 1 and ensure adequate access to
breakthrough medication.
5
Patient follow-up and reassessment,
especially during the first 7–14 days to fine
tune the total daily dose and the round-the-
clock long-acting dosages accordingly.
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Opioid Analgesics 351
carefully titrated to avoid withdrawal effects[117].
Other treatment options include changing from
opioid to non-steroidal anti-inflammatory agents
for pain relief, anti-dopamine agents such as
droperidol and anaesthetic agents such as propofol
[174, 180].
Constipation is unique among all the complications
with minimal tolerance. About half of patients
on oral morphine reported some alterations in
bowel habits, with a NNH of 4.6 [133]. Both
the central and the enteric nervous systems carry
opioid receptors which induce non-peristaltic gut
contractions, resulting in prolonged intestinal
transit time and increased water re-absorption.
e treatment of opioid-induced constipation is
largely a matter of trial and error. Classical methods
include oral hydration, dietary fibres and a variety
of laxatives such as stimulants (e.g. bisacodyl
or senna), osmotic agents (e.g. lactulose), stool
softeners (e.g. ducusate) and enemas [173]. Using
alternative routes of opioid administration, such as
the spinal or transdermal, has been advocated but
there is limited evidence of effectiveness. Synthetic
oral opioid antagonists with negligible systemic
absorption have been under intensive clinical
studies. N-methylnaltrexone and alvimopan have
been shown to reverse opioid-induced constipation
as well as postoperative ileus without affecting the
opioid analgesia [33, 62, 104].
Specic Side Eects of Long-
term Prescription
It is common clinical observation that opioids can
induce sedation. Clinical studies on healthy subjects,
cancer and non-cancer pain patients on long-term
opioids demonstrated features of impaired arousal,
concentration and attention upon psychomotor
testing [44, 96, 168]. is should be interpreted
with caution, as illnesses, pain and mood changes
may also induce cognitive dysfunction themselves,
and chronic opioids therapy may actually normalise
the dysfunction as reported in cohort studies [107].
Specific tasks, such as driving, were not impaired, as
psychomotor testing did not revealed any difference
in driving ability between chronic opioid users
(with cancer) and non-users [183]. Other studies
on chronic opioid users (with non-cancer pain)
and methadone maintenance therapy subjects have
also failed to identify any significant impairment
during driving simulation [66, 73].
e hormonal changes with long-term opioids have
been known for decades. Sex hormone levels were
reduced in methadone maintained subjects and
chronic pain patients receiving intraspinal opioids
[119, 130], while patients on oral opioid analgesics
are relatively spared [131]. Other hormonal
disturbances include reduced prolactin and cortisol
release, and metabolic effects include dyslipidemia,
glucose intolerance and fluid retention [36, 69,
111, 195, 204].
Opioids may also contribute to the metabolic
complications of human immunovirus (HIV)
patients [47]. e clinical implications of endocrine
adverse effects have been recognised only recently,
and regular monitoring of endocrine status and
hormonal replacement therapy for patients on
intrathecal opioids have been advocated by some
[2]. ese endocrine changes are not always
detrimental and may explain the improved
outcome with opioid use during stressful situations
like myocardial infarction [49] or postoperative
state [81].
Pharmacokinetic Data
e following table (Table 21.04) is extracted from
various studies with single intravenous boluses.
e kinetic data of methadone, propoxyphene and
fentanyl may change with drug accumulation after
repeated dosing.
Morphine, codeine and their
metabolites
is is a synopsis of several opioids of
pharmacological development interest. In the
following discussion, efficacy is expressed in
number needed to treat (NNT) and figures are
quoted from e Oxford League table of Analgesics
unless otherwise stated.
Few drugs have enjoyed the same success as
morphine. It was the first plant alkaloid isolated and
it forms the basis of pharmacological modifications
leading to a range of opioid analgesics [32]. Part of
the success lies in its versatility of application. It can
be sniffed, ingested (with oral availability of 20–30%
[114]), injected intravenously, intramuscularly,
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352 Ming Chi CHU
subcutaneously, epidurally, intrathecally and even
deposited perineurally or topically [202]. e
pharmacokinetics vary significantly according
to the preparation, the route of administration,
patient gender and presence of liver or renal failure
[74, 109, 158, 176].
Morphine is effective in managing a variety of
painful conditions such as postoperative pain
(with a NNT of 2.9), trauma, chronic cancer and
non-cancer pains [53, 123], and acute treatment
for myocardial ischaemia. It is also used as a
general anaesthesia adjunct for cardiac surgery,
or as a sedative in the intensive care setting [152,
161]. Morphine is metabolised by both the liver
and the kidneys into two major metabolites with
contrasting actions, morphine-3-glucuronide
(M3G) and morphine-6-glucuronide (M6G). In
animal studies, M3G has no analgesic properties
and has been associated with antagonism of
morphine analgesia, as well as neuropathic features
like allodynia [4].
It has been known for many years that M6G has
even greater analgesic potency than morphine
and may be partly responsible for the actions of
the parent drug. Experimental and clinical studies
suggested that it is pharmacologically distinct from
morphine [184]. Oral M6G is poorly absorbed, yet
extensively hydrolysed back to morphine and acts
accordingly [141]. When given intravenously, it has
a much lower volume of distribution than morphine.
Delay in crossing the blood-brain barrier is partially
compensated by molecular folding and possibly
an active transport system. It is predominantly
excreted by the kidneys and accumulation occurs in
renal failure. Intravenous M6G is less potent than
morphine at a potency ratio of 1:3 to 1:10, but when
given intrathecally (in animals), the potency increase
drastically to more than 300 times that of morphine.
e mechanism is not clearly explained, as both
chemicals act on mu receptors and are reversible
with naloxone. Different mu receptor subtypes have
been postulated as specific sites of action for M6G
and may account for such differences.
Another interesting feature is the safety profile. It
causes much less nausea and vomiting (~ 10–20%
at clinical doses) than morphine, minimal sedation
and is probably less depressant on the respiratory
drive as well [4, 34, 85]. Clinical interest, however,
comes at a price; like all new drugs the price tag is
prohibitive, being 800 times more expensive than
morphine (circa 1994, [114]).
Codeine is discussed here as it is metabolically
related to morphine. It is another naturally
occurring plant alkaloid that enjoyed popularity
as an antitussive and “weak opioid” among
paediatricians, neuroanaesthetists and paediatric
anaesthetists [196]. Oral or rectal bioavailability
is good at 90%. Single-dose codeine is a mild
analgesic for postoperative pain with a NNT
of 16.7 (improves to 4.4 when combined with
Table 21.04 Kinetic data of opioids
Volume of distribution
(L/kg)
Clearance (ml/kg/min) Elimination half-life
(hour)
Codeine
3.6 12 3.5
Morphine
1.9 22.5 2
Morphine-6-glucuronide
0.2 1.9 1.4
Fentanyl
5.9 20 6
Pethidine
4.4 17 3.2
Tramadol
2.9 6.5 5
Methadone
3.6 1.7 27
Propoxyphene
2.5 16 2.66
Remifentanil
0.3 60 0.13
(References: [31, 72, 77, 89, 127, 184, 196].)
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Opioid Analgesics 353
paracetamol).Until recently, the clinical efficacy
of codeine was attributed to its active metabolite,
morphine, via O-demethylation by cytochrome
P450-2D6 [35]. Population variations in P450-
2D6 expression lead to clinical variations in codeine
metabolism. About 12–21% of Caucasians (and
1% of Asians) are “poor metabolisers”, and up to
5% of Caucasians (and 2% of Asians) are “ultra-
rapid metabolisers” [194]. While case reports of
clinical non-responders and toxicities have been
associated with such genetic polymorphism, the
correlation is far from clear [197]. Some authors
cast doubt on the significance of P450-2D6 as it
only accounted for 5% of codeine metabolism and
objective measurements on mu activity (miosis)
did not correlate with plasma morphine level [7,
108]. More work is needed to elucidate the exact
mechanisms of action of codeine. Side effects of
codeine are similar to other opioids and respiratory
depression has been reported in infants receiving
codeine for cough suppression [126, 196].
Fentanyl
Fentanyl is the first synthetic phenylpiperidine with
potent (100 times of morphine) opioid activity.
It is highly lipid soluble with an octanol:H
2
O
coefficient of 816 (1.4 for morphine), resulting
in rapid passage across tissue barriers and rapid
onset-offset of clinical effects [140]. Prolonged
infusion, however, can lead to drug accumulation
and prolonged action (Fig. 21.01). e unique
pharmacokinetic profile makes it an ideal agent
for short-term analgesia such as postoperative
pain, procedure-related pain or breakthrough pain
in cancer patients [11, 203], but limits its role
in chronic pain management. A number of drug
delivery modifications have been developed to
overcome this barrier.
e therapeutic transdermal system (TTS) consists
of a fentanyl-loaded reservoir and a rate control
adhesive membrane. After topical application, it
delivers a steady flow of fentanyl across the dermis
and forms a slow-release intradermal depot [76].
It is too slow for postoperative pain management
and is primarily used for treatment of chronic pain.
Clinical trials with cancer pain patients revealed
similar efficacy and probably less constipation with
TTS fentanyl when compared with oral morphine.
e role of TTS fentanyl in chronic non-cancer
pain is still controversial [98] and abuse of fentanyl
in the leftover patches has been reported.
Another transdermal fentanyl device, the patient-
controlled transdermal system has become available
recently. It consists of a battery-driven iontophoretic
patch that delivers a 40 mcg bolus of ionised fentanyl
upon triggering. Pharmacokinetic and analgesic
profiles are comparable with intravenous fentanyl
infusion for postoperative pain management [38].
Oral transmucosal fentanyl citrate is another non-
invasive delivery system where the drug is absorbed
via the buccal mucosa leading to a rapid onset of
action (usually within 15 minutes). Meta-analysis
has confirmed its superiority over oral morphine
in treating breakthrough pain in cancer patients,
as well as acute pains in patients without venous
access such as sickle cell crisis or burns [8, 125].
Fentanyl has also been administered intrathecally
and epidurally for labour analgesia and postoperative
analgesia. Its stress reduction effects are applied
when it is administered during endotracheal
intubation [63], neuroleptangesia [25] or cardiac
anaesthesia [161]. Side effects are similar to other
opioids, although high-dose fentanyl is associated
with muscle rigidity [188], which is correctable
with muscle relaxation.
Pethidine (meperidine)
Another synthetic opioid, originally designed as an
atropine analogue, pethidine quickly became one
of the most popular analgesics. It is effective for
postoperative pain management with a NNT of 2.9.
Its relative lipid solubility and mild local anaesthetic
property make it particularly suitable for epidural
use [127]. It is also unique among all the opioids in
that it has anti-shivering effects [51]. e half-life of
pethidine is about 3 hours. It is demethylated in the
liver to norpethidine, which is then excreted by the
kidneys. e half-life of norpethidine is about 15
to 30 hours. Convulsion and even deaths have been
attributed to norpethidine toxicity in both animal
and human studies, especially in the presence of
renal impairment [145, 150]. Another potential
complication of pethidine is the interaction with
monoamine oxidase inhibitors causing serotonin
syndrome that may lead to death [70].
Despite all the shortcomings, pethidine is still a
popular analgesic in certain clinical settings. It is
still commonly used in the labour ward in view of
its low cost and familiarity, but it does not offer
better analgesia and respiratory depression of the
newborn has been reported [28, 115, 151]. Another
commonly held belief is that pethidine induces
less sphincter of Oddi spasm than other opioids,
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354 Ming Chi CHU
although current clinical data do not support this
notion [179]. ere is a growing trend to reduce
the use of pethidine worldwide, especially in elderly
patients [128, 132].
Tramadol
Tramadol is another example of a synthetic
opioid with non-opioid activities [77]. e parent
chemical’s affinity for the mu opioid receptor is
6,000 times less than morphine, and its opioid
actions are predominantly mediated by one of its
active metabolites, M1, via a similar pathway as
codeine (see above). Other mechanisms of analgesia
include inhibition of nor-adrenaline and serotonin
re-uptake. e NNT for acute postoperative pain
is about 5, and PCA studies have suggested an
equianalgesic ratio of 6:1 to 10:1 with intravenous
morphine [103]. Tramadol is excreted in urine and
the metabolites from the liver; and dose adjustment
is necessary in the presence of liver or renal failure.
e lack of mu activity is theoretically advantageous
in two aspects: improved safety with less respiratory
depression and reduced potential for abuse. While
the former claim is confirmed with controlled
clinical trials [187], respiratory depression has been
reported in individuals with renal failure [18].
Similarly there has been growing concern for the
abuse potential of tramadol following case reports
of abuse by patients and physicians [169, 199],
despite surveillance studies confirming the low
overall incidence of abuse of tramadol [43].
Other commonly reported side effects are nausea
and dizziness. Withdrawal symptoms (mostly
similar to opioid withdrawal) do occur occasionally
[163], and serotonin syndrome has been reported
in patients receiving serotonin re-uptake inhibitors
[101].
Methadone (Physeptone)
Initially synthesised by the Germans during the
Second World War, methadone’s analgesic properties
were not known until many years later. Methadone
is unique among opioids as it has significant NMDA
receptor antagonistic properties [56, 57]. is may
explain the relatively low incidence of tolerance
and withdrawal symptoms compared with other
opioids. Its pharmacokinetics profile also differs
from other opioids with two main features: it has a
relatively long half-life (15–55 hours) and high oral
bioavailability (60–85%) [29]. Both features make
it ideal for the maintenance management of heroin
addiction and it has been the accepted treatment
for over 40 years [73].
Its use as an analgesic, however, is largely limited
by its variable pharmacokinetics, as well as the
social stigma of its being labelled as the “addict’s
drug” [10]. ere has been a resurgence of
interest in using methadone for analgesia since its
pharmacokinetics have been better understood and
NMDA receptor antagonist properties recognised
[190]. e exact contribution of its anti-NMDA
receptor properties to the overall analgesia is still
unknown [57]. As the NMDA receptor is involved
in the pathogenesis of neuropathic pain, there was
high hope of using methadone for the treatment
neuropathic pain. While it had been shown to be
useful for neuropathic pain states, its effectiveness
is no better than other opioids [65, 121].
Another clinical development is the isolation of l-
(or R-) methadone, the active isomer; (d- (or S-)
methadone also binds to the NMDA receptor but
not to the mu receptor) [90]. e efficacy and side-
effect profile of l-methadone is similar to racemic
methadone [186], and has been used in pain
management [156] and maintenance therapy [50].
Propoxyphene
Propoxyphene is a synthetic analogue of
methadone with much lower potency and oral
availability (at 30%). It is metabolised by the liver
to nor-propoxyphene, which is renally excreted,
and accumulation of both the parent drug and
nor-propoxyphene occur in renal failure [37].
Like methadone, it has weak NMDA receptor
antagonist properties although the clinical
significance is unknown. While the NNT of 65 mg
propoxyphene for acute pain is 7.7, it improves to
4.4 when combined with paracetamol [45], and its
side effects are well tolerated [72].
It has a low potential for abuse due to its minimal
psychomimetic effects [201] and severe tissue
irritation during parenteral injections [177].
Propoxyphene has become one of the most
popular “weak” opioids for postoperative and
chronic cancer pain management [120]. It is so
commonly available that attempted suicide from
dextropropoxyphene overdose has become a public
health issue in the UK and Scandinavia [102, 167].
Fatalities with propoxyphene can be multifactorial.
Apart from the opioid effects, propoxyphene also
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Opioid Analgesics 355
has local anaesthetic actions on the myocardium
causing bundle branch blocks, prolonged QRS
and cardiac arrest at oral doses above 1 g [3, 85].
Treatment should include naloxone (for opioid
effects), general supportive measures, treatment of
arrhythmias, recognition of concomitant multi-
substance overdose and enhanced drug elimination
by haemodialysis [200].
Remifentanil
Remifentanil presents with unique
pharmacokinetics and clinical features. It has a
relatively low pKa (of 7.26) and is predominantly
un-ionised in physiological pH, thus ensuring a
rapid onset of action of about 1 minute [21]. e
molecular structure is easily hydrolysed by non-
specific esterases and is not affected by diseases (e.g.
pseudocholinesterase deficiencies) or medications
(e.g. cholinesterase inhibitors).
Computer simulation predicts a persistently low
context sensitive half-time of 3 to 6 minutes (Fig.
21.01), which is unaltered with age or organ
failures. ese pharmacokinetic features make it
ideally titratable for clinical scenarios that require
rapid analgesia and emergence, such as fast-track
cardiac surgery, neurosurgery and day surgery
[162]. It is also used to facilitate insertion of
laryngeal mask airways, endotracheal intubation
and sedation for minor surgical procedures.
Sedation with remifentanil in the intensive care
setting may facilitate weaning of ventilation and
shorten the stay of neurosurgical patients [19]. Its
rapid offset also provides an ideal property as an
experiment tool for the pharmacology of opioid
withdrawal [5].
e cessation of remifentanil infusion may lead
to a rapid resurgence of pain and longer-acting
analgesic is mandatory if postoperative pain
management is required. Current preparations
contain glycine, which precludes neuroaxial
administration, and infusion equipment is needed
for intravenous infusion. Despite its short half-
life, the psychocognitive effects may outlast the
analgesic effects for up to 1 hour [26].
Prescription Behaviour with
Opioids
Understanding the pharmacology is only one
of the factors that influence the prescription
behaviour of doctors. ere is great variation
in opioid dosage in different pain states [157]
and the dose prescribed may not correlate to the
Figure 21.01 Context sensitive half-time for fentanyl and its analogues. Reproduced with the permission of
T.D. Egan [58].
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356 Ming Chi CHU
pain intensity [182]. Findings during the pain
assessment, ethnicity [39, 175], age [9], patients’
suffering and pain behaviours [182] may affect
the prescription pattern. Staff familiarity with the
medication [132], staff seniority (the less senior
the more likely to prescribe [86]), a subjective
belief about patients’ behaviour [23] and concerns
about prosecution [135] also play significant roles
in staff’s prescription behaviour, sometimes even
against established guidelines [46].
Fear about tolerance and addiction with medically
prescribed opioids may lead to hesitation in the
release, prescription and taking of opioids for pain
management [55, 92], a phenomenon known as
“opiophobia”. Morphine seems to suffer most in
Figure 21.02 National trends in opioid prescriptions in the United States 1997–2002. Note the decreasing
trend of pethidine prescription [71, 93].
Figure 21.03 Opioid prescription data from a regional teaching hospital in Hong Kong. (Data from the
pharmacy of the Prince of Wales Hospital, Hong Kong).
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Opioid Analgesics 357
this aspect, as it is most commonly under-dosed
compared with other opioids [129]. Apart from
inadequate pain relief, suboptimal prescription
may precipitate aberrant drug-seeking behaviours
that are virtually indistinguishable from those
of addiction without pain. is is referred to as
“pseudoaddiction” and may lead to a breakdown in
the doctor-patient relationship [110, 193].
Opioids, Chronic Pain and
Substance Use Disorder
With education and understanding, both legislators
and clinicians have become more accepting of
the use of opioids for pain management over the
recent decades as demonstrated by the increasing
global trends of opioid prescriptions (Figs. 21.02
and 21.03). e increasing popularity of opioids
has raised concerns about diversion and abuse of
prescription opioids among the general public.
A survey in South Australia highlighted the deaths
associated with the medical use of methadone
for pain management [198]. is was echoed by
a report of an increase in opioid abuse over the
recent decade in the United States where up to
4.8% of the general population has reported abuse
of prescription analgesics (http://oas.samhsa.gov/
NSDUH/2k5NSDUH/2k5results.htm#2.16).
It was worrisome to note that more than half of
these prescription opioid abusers obtained the
drug from a friend or relative, and less than 20%
from their doctors. About 8 billion US dollars was
spent in 2001 for medical treatment, loss of work,
legal proceedings and correctional services for these
abusers [24]. e association between abuse and
opioid prescription, however, should be interpreted
with caution, as a similar increase in non-opioid
abuse was also observed in the same period.
e presence of chronic pain complicates the
issue. First, there is the problem of defining abuse
or addiction in the presence of chronic pain.
Conventional definitions (DSM-IV-TR) include
phrases like “maladaptive pattern of substance
use” according to expert opinion are subjected to
different interpretations (Tables 21.05 and 21.06).
e classical characteristics of abuse, namely,
tolerance and dependence, are common in chronic
opioid users, and both addiction medicine and pain
experts question their validity to define opioid abuse
in this group. Newer definitions which address the
controversy by avoiding these pain-related clinical
features have been recommended (see Table 21.07).
It was also advocated that addiction in chronic
pain patients is best diagnosed and managed after
reasonable attempts at pain management (including
use of opioids) have been tried.
Table 21.05 Correlation between aberrant drug-
related behaviours and addiction [146]
Probably more
predictive
Probably less predictive
Selling prescription
drugs
Aggressive complaining
for more drug
Prescription forgery Reporting unintended
psychic symptoms
Recurrent prescription
losses
Drug hoarding when
symptoms improve
Obtaining drugs from
non-medical sources, or
stealing or “borrowing”
from others
Openly acquiring
similar drugs from other
medical sources
Injecting oral
formulations of
analgesics
Requiring a specific
drug
Concurrent illicit drug
use
Unapproved use to treat
other symptoms
Multiple dose
escalations or non-
compliance despite
warnings
Occasional dose
escalation or non-
compliance
Resistance to changes
despite clear evidence
of adverse effects
Resistance to change
for fear of symptom
aggravation
Table 21.06
Behaviours associated with addiction
and pseudoaddiction [110]
Addiction Pseudo-addiction
Using analgesics
prescribed for others
Disputes and arguments
with staff on treatment
Injecting analgesics Significant requirement
for pain treatment
Passive or emotional
coping strategies
Active behavioural
coping strategies
Illicit drug use
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358 Ming Chi CHU
And then there is the problem of collecting data
on the incidence of opioid abuse in chronic pain
patients. While previous retrospective reports of
acute pain patients (with burns or medical illnesses)
suggested a very low incidence of opioid abuse
(0–0.04%) [143, 147], recent studies reported
figures of about 1.4–5% for chronic non-cancer
pain [48, 87]. is rate is similar to the prevalence
of prescription analgesic abuse among the general
population (see above). In general, current data do
not indicate an increased incidence of opioid abuse
in chronic pain patients when compared with the
general population.
Patients with a history of substance use disorder pose
special challenges for pain clinicians. Compared with
addicts who do not have any pain condition, they
tended to be older, use less injectable medications,
and have a more complicated psychosocial
background and substance use pattern [27]. ere
is little doubt that patients with substance use
disorders do have pain [91, 155] and successful
opioid therapy in those with a demonstrable source
of pain has been reported without detrimental
effects [113, 138]. As there is little quality evidence
Table 21.07 Definitions for opioid users according
to the consensus statement from the American
Academy of Pain Medicine, the American Pain
Society, and the American Society of Addiction
Medicine [159]
Addiction is a primary, chronic, neurobiologic
disease, with genetic, psychosocial, and
environmental factors influencing its development
and manifestations. It is characterized by
behaviors that include one or more of the
following:
• Impaired control over drug use,
• Compulsive use,
• Continued use despite harm, and
• Craving.
Physical dependence is a state of adaptation that
is manifested by a drug class specific withdrawal
syndrome that can be produced by abrupt
cessation, rapid dose reduction, decreasing blood
level of the drug, and/or administration of an
antagonist.
Tolerance is a state of adaptation in which
exposure to a drug induces changes that result in
a diminution of one or more of the drug’s effects
over time.
Table 21.08 Guidelines on prescribing opioids for
patients with an addiction history [192]
Outline goals and practice of opioid therapy,
document with the opioid contract and inform
relevant medical parties of the contract.
Document all prescription dosages and rationale
for subsequent changes.
Titrate opioid dose to achieve functional goals.
Consider non-opioid adjuncts.
Prescribe adequate amounts until follow-up; avoid
refills.
Monitor for signs of non-compliance or abuse.
Urine samples for drug testing may be useful.
Increase frequency of reviews if there are signs of
non-compliance.
Engage patients’ family and friends on monitoring
and reinforcing compliance.
Formulate plans in case of violation of opioid
contract, including warnings, weaning off opioids,
referral to addiction medicine specialists or legal
authorities.
on the clinical outcome, we are left with expert
opinions and guidelines (see Table 21.08) with a
variable degree of conservatism [14, 106, 171].
Indeed it has been commented that the relevant
medical literature and practice are dominated by
opinion, tradition, myths, cultural norms and
regulatory pressures rather than evidence [105,
181]. Clinicians are expected to exercise judgement
in balancing the risk of abuse with the benefits of
analgesia for individual patients [134].
Extremes of Age, Labour and
Lactation
Opioids given during labour are invariably
delivered to the fetus and theoretically may affect
neonatal outcome [115]. e most extensively
studied opioid is pethidine, which is associated
with respiratory depression and depressed suckling
behaviour [22, 80]. Other systemic opioids such as
morphine, fentanyl and remifentanil have also been
associated with neonatal respiratory depression,
while neuroaxial opioids appeared safe [95].
Withdrawal symptoms may occur in neonates
delivered from mothers who are on long-term
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Opioid Analgesics 359
opioids. In one study, up to 58% of babies from
mothers on methadone maintenance therapy and
11% of those from methadone analgesic-user
mothers developed withdrawal symptoms [164].
e general condition of the babies was considered
good and they did not require resuscitation. e
routine use of naloxone in these babies is not
evidence-based and therefore is not advised [116].
Opioids administered by all routes are generally safe
for both the mother and the baby during lactation
[16]. Most of the opioids are excreted in minimal
quantities, and with low oral bioavailability the
uptake of the drug is clinically negligible in the
neonate. As nor-pethidine may accumulate in
neonates, it is advised to avoid pethidine in the
lactating period.
Opioids are effective analgesics for elderly patients
[9]. e major difficulty in this population is the
management of side effects. Some studies have
demonstrated an increased risk of hip fractures
associated with recent use of opioids [165]. Other
significant side effects for the elderly include
constipation, urinary retention and drug interactions
with sedatives or antidepressants. Physicians should
start at low doses at regular intervals and titrate the
dose requirement with small increments. Patients
should be monitored closely for the initial period
and side effects treated aggressively.
Opioids which produce neurotoxic metabolites
such as pethidine and partial agonists that may
precipitate withdrawal such as pentazocine should
be avoided [17]. ere is ongoing controversy
regarding the use of propoxyphene for the elderly.
e American Geriatrics Society has highlighted
its potential neurological side effects and caution
against its use [1]. is was largely based on expert
opinion, as published clinical data did not show
an increased risk in the elderly [72]. With careful
patient selection and drug titration, other experts
have argued that the clinical benefits will still
outweigh the risks and opioids shall remain a viable
option for geriatrics pain management [139, 160].
Summary
Studies on opioid receptors have improved our
understanding of clinical phenomena such as
tolerance and hypersensitivity. ey have also
laid the foundation for the development of newer
agonists and antagonists.
e clinical use of opioids, however, remains a matter
of individual judgement. Significant variations in
pharmacokinetics, dynamics, physiological status,
as well as the clinician’s beliefs and concerns, have
all influenced the overall prescription pattern for
opioids.
Development of opioid chemicals aims at
improvement in kinetic properties, better analgesia,
as well as improved safety. e ideal opioid has yet
to be found.
Acknowledgement
e author would thank Ms. Jasper Wong,
Department of Pharmacy, Prince of Wales Hospital,
Hong Kong, for her assistance in data collection.
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