Support Care Cancer (2005) 13: 153–159

DOI 10.1007/s00520-004-0690-6 REVIEW ARTICLE

Geoffrey K. Gourlay
Advances in opioid pharmacology

Received: 18 March 2004

Accepted: 9 August 2004
Published online: 21 December 2004
# Springer-Verlag 2004
G. K. Gourlay (*)
Pain Management Unit, Department of
Anaesthesia and Pain Management,
Flinders Medical Centre, The Flinders
University of South Australia,
5042 Bedford Park,
South Australia, Australia
e-mail: Geoff.Gourlay@Flinders.edu.au
Tel.: +61-8-82017703
Fax: +61-8-83741758
Abstract Natural and synthetic opi-
oid compounds, either alone or in
combination with other drugs, are
widely used analgesics for patients
with both acute and chronic pain.
Decades of extensive pharmacologic
investigations have characterized
three high-affinity cell-surface neuro-
nal receptors, the activation of which
is responsible for both the desirable
properties (antinociception) and un-
desirable properties (respiratory de-
pression, nausea and vomiting,
dependence, etc.) of opioid drugs.
Recent research in molecular biology
and pharmacogenetics in relation to
opioids and their receptors has helped
clarify previous pharmacologic ob-
servations and has laid the ground-
work for new analgesic therapies with
improved therapeutic outcomes.
Keywords Opioids . Pharmacology .
Receptors . Metabolism

Introduction endorphins) and, secondly, of their corresponding recep-

Opium and its derivative alkaloids have been known to
relieve pain and alter mood since the advent of recorded
history. For centuries, these agents have been integrated
into medical practice with varying efficacy. Recent devel-
opments in opioid pharmacology and molecular biology
promise to make this class of compounds even more
clinically useful. New insights into receptor biology,
pharmacogenetics, and pharmacologic antagonism may
refine the use of established opioids and point toward the
development of more selective compounds with improved
clinical characteristics. Such improvements should be
especially beneficial in treating patients with chronic pain,
such as cancer pain.
New concepts in opioid receptors
The most important neurotransmitter system involved in
nociception is composed, firstly, of the endogenous opioid
peptides (endomorphins, enkephalins, dynorphins, and
tors, which are expressed within specialized neurons of the
ascending and descending pain transmission and inhibition
systems in the spinal cord, brainstem, medulla, periaque-
ductal grey substance, thalamus, limbic system, and
cerebral cortex [1, 2].
The existence of three distinct opioid receptors was
originally deduced from the different pharmacologic ef-
fects of various opioid agonists and antagonists that se-
lectively induce or inhibit different physiologic responses,
both experimentally and clinically [3–5]. Three separate
receptors—μ (mu), δ (delta), and κ (kappa)—were iden-
tified on the basis of pharmacologic response, in vitro
radioligand binding affinities, and in vivo localization of
labelled drug in tissue homogenates or sections [4–7]. This
allowed opioids to be grouped according to similarities
in the activation of their receptor types. Although all an-
algesic agonists are bound by more than one receptor type
with varying degrees of affinity, the result is distinct dose-
response characteristics for each agonist while at the same
time accounting for the full range of recognized phar-
macologic properties of each agent [1]. The μ-agonists
154

are responsible for analgesic properties at both spinal and Table 1 Opiate binding affinities. Note: the smaller the number, the
supraspinal sites, as well as for dependence, euphoria, greater the binding affinity for a particular receptor. Adapted from
reference 18 (ND, no data)
respiratory depression, sedation, miosis, and tolerance. The
δ-agonists, on the other hand, are associated with analgesia Opiate Affinity (Ki, 10−9 M) in the guinea pig
and euphoria, whereas the κ-agonists produce analgesia, μ δ κ
miosis, sedation, and, in contrast to the other receptors,
dysphoria [8, 9]. Morphine 1.8 90 317
Subsequently, similar observations led investigators to Normorphine 4.0 310 149
postulate the existence of multiple subtypes of each of the Levorphanol 0.6 5.6 9.6
three opioid receptors. Two subtypes of the μ-receptor (μ1 Codeine 2,700 >10,000 ND
and μ2) were initially proposed to explain how opioid Methadone 4.2 15.1 1,628
receptors demonstrated two different levels of in vitro Fentanyl 7.0 151 470
binding affinity, and how treatment with the μ-receptor Pethidine 385 4,345 5,140
antagonist naloxazone (an irreversible ligand) abolished Pentazocine 7.0 106 22.2
only the very high-affinity binding—i.e. the binding Buprenorphine 0.6 1.3 2.0
associated with typical opiate analgesia, or μ1. Lower Naloxone 1.8 27 17.2
affinity binding persisted for the μ-agonists as well for the
δ-agonists through a second, lower affinity μ-receptor, μ2
[10]. Pharmacologically, each subtype was purported to receptor types are highly conserved, whereas the extra-
be responsible for a portion of the responses typical of cellular loops are significantly dissimilar, and the primary
μ-agonist binding. Activation of the μ1-receptor is linked structure of each N-terminal extracellular segment is
to supraspinal analgesia, hypothermia, and prolactin re- essentially unique [21, 22]. Figure 2 depicts the same
lease, whereas activation of the μ2-receptor is responsible complex from above [11]. The highly conserved trans-
for spinal anaesthesia, respiratory depression, delayed membrane helices are arranged into the opioid binding
gastrointestinal tract transit, sedation, and bradycardia pocket. The poorly conserved extracellular loops provide a
[11]. Similar evidence has been used to support the ex- chemicophysical explanation for ligand discrimination due
istence of δ- and κ-receptor subtypes [12, 13]. to differences in noncovalent binding sites. The relatively
However, the presence of different receptor subtypes conserved intracellular loops and distinctive C-terminal
has been challenged by the failure to locate individually tails help account for the overall general similarities, as
distinct genes. Only three opioid receptor genes have been well as for the type-specific differences that occur in
isolated and cloned—a μ-receptor gene (MOR-1), a δ- intracellular signalling via G-coupled adenylyl cyclase
receptor gene (DOR-1), and a κ-receptor gene (KOR-1)
[14–16]. In addition, a variety of localization techniques
have demonstrated that each receptor type is expressed in
a distinct, but variably overlapping, distribution [17]. The
in vitro binding studies that suggested their existence had
been performed with crude tissue homogenates containing
more than a single receptor type. In light of this diver-
gence between the pharmacologic and molecular tech-
niques, three alternative hypotheses have been proposed
to account for opioid analgesia: (1) nearly all pharmaco-
logic and endogenous opioids bind to the high-affinity,
naloxone-sensitive μ1-receptor with similar affinity as
the source of analgesia [8]; (2) agonist binding affinities of
the three receptor types result in the analgesic response
[18]; and (3) receptor splice variants or receptor homo-
dimers and heterodimers might be responsible for anal-
gesic response [19, 20]. Table 1 lists the binding affinities
of different agonists and antagonists to the three opioid
receptors. Although the binding affinity is greatest to the
μ-receptor for each compound, variable (and often signif-
icant) binding occurs with the δ- and κ-receptors as well
(Table 1) [18].
Fig. 1 Cloned μ-, δ-, and κ-receptors from mammalian cells. Dark
Figure 1 demonstrates the degree of homology at each circles signify the same residue in all three opioid receptors, light
amino acid site from mammalian cells [21]. The trans- circles signify the same residue in two of three receptors, and
membrane domains and intracellular loops of all three open circles signify a unique residue. Adapted from reference 21

Fig. 2 How fentanyl might fit into the binding pocket of the μ-
opioid receptor between the seven transmembrane domains.
Adapted from reference 11
inhibition, ion channel modulation, and mitogen-activated
protein (MAP) kinase activation. Activation of all three
receptors leads downstream to decreased neurotransmitter
release and nociceptive impulse propagation [23, 24].
Although there is no evidence that specific genes
encode receptor subtypes, observed pharmacologic diver-
sity and differences in localization may be the result of
receptor species that arise from alternatively spliced mes-
senger ribonucleic acid variant transcripts, post-transla-
tionally modified proteins [25], or receptor homodimers or
heterodimers [19, 20]. Dimerization might result in varied
individual response and incomplete cross-tolerance and
may be the basis for the utility of opioid rotation for
chronic use, such as for cancer pain. The relevance of
alternatively spliced opioid receptor variants [24, 17] and
dimerization is still controversial.
The identification and cloning of the three opioid
receptors made it possible to study each receptor in
isolation. Mutant mice lacking the individual correspond-
ing genes (i.e. knockout mice) were generated using
homologous recombination [26–28]. Any disruption in an
opiate receptor produced mice with absent binding of
selective agonists for that receptor type. Mice deficient in
one, two, or all three receptors have been generated [29]
and their physiologic and behavioural responses to various
agonists have been studied. The absence of one receptor
type does not markedly alter the expression of the other
two, although the potential exists for changes in receptor/
G-protein coupling efficiency. It is even possible to study
the effects of disrupting various portions within the same
gene. It should be noted, however, that different results
can still be obtained with targeted knockouts of the same
gene in different mice, due to subtle differences in the
extent of the genetic disruption that is produced either in
the coding region itself or in its controlling elements [30].
Particular opioids have been identified pharmacologi-
cally as prototypically selective agonists for each of the
155
three receptor types. The activities of highly selective μ-,
δ-, and κ-agonists should be eliminated in MOR-, DOR-,
and KOR-deficient mice, respectively, and any residual
responsiveness should be interpreted as evidence of cross-
activation of the nondisrupted receptors. For example, in
MOR-deficient mutants, the analgesic effect of morphine
is abolished. Respiratory depression, naloxone-precipi-
tated withdrawal, and reward are also absent, and mor-
phine administration becomes adversive, perhaps due to
weak binding of morphine at the κ-receptor. Conversely,
morphine analgesia is intact in DOR- and KOR-deficient
mice. Interestingly, μ-receptors are required, to a variable
extent, for full responses to δ-agonists, suggesting an
interdependence or cross-reactivity between μ- and δ-re-
ceptors. The results of morphine administration in μ-
receptor knockout mice demonstrate that morphine effects
do not require δ- or κ-receptors [21].
The knowledge obtained from molecular genetic in-
vestigation may point towards the development of new
opioid agonists with improved pharmacologic properties
for clinical use. Unfortunately, because μ-receptor activa-
tion by itself is responsible for both the analgesic, as well
as the adverse, effects of morphine, it may not be ther-
apeutically possible to separate the desired from the un-
desired effects [31]. On the other hand, the existence of
pharmacologically (as opposed to genetically) distinct re-
ceptor subtypes may offer the possibility of creating more
selective and less toxic opioids for therapeutic use.
Metabolism of opioid drugs
The opioid alkaloids are extensively metabolized mainly
in the liver (morphine is mainly metabolized in the gut
wall during absorption following oral administration) and
predominantly excreted via the kidneys [18]. There are
two main types of reactions: oxidations (catalyzed by
cytochrome P450) [32, 33] and conjugations (catalyzed by
transferases such as UDP-glucuronyl transferase). Opiates
(drugs with a morphine-like structure) with a hydroxyl
group at the 3-position are metabolized by glucuronida-
tion, whereas those with substitution of the C3 hydroxyl
(e.g. a methyl group such as in either codeine or ox-
ycodone) undergo an oxidative demethylation prior to
glucuronidation. Ester-type opioids (e.g. heroin) are rap-
idly hydrolyzed by tissue esterases. Table 2 gives the
major routes of biotransformation and major metabolites
for commonly prescribed opioids [18, 33–35].
Cytochrome P450
A number of commonly used opioid analgesics (e.g.
codeine, fentanyl, sufentanil, methadone) are oxidized
in the liver by microsomal cytochrome P450 (CYP450)
enzymes as their major route of biotransformation. Cur-
156
Table 2 Metabolism of opioids used for cancer pain. Sources: references 18, 33–35
Opioid Primary metabolic pathway
Morphine Hepatic glucuronide conjugation by UDP glucuronyl transferase
Codeine Hepatic oxidative O-demethylation by CYP2D6
Oxycodone Hepatic oxidative O-demethylation by CYP2D6
N-demethylation by CYP3A4 and reduction
Levorphanol Hepatic glucuronide conjugation
Hydromorphone Hepatic glucuronide conjugation
Fentanyl Hepatic oxidative N-dealkylation by CYP3A4
Methadone Hepatic oxidative N-demethylation by CYP3A4
Heroin Sequential two-step deacetylation by various tissue esterases
Propoxyphene N-demethylation by CYP3A4
Meperidine N-demethylation by CYP3A4
rently, 49 separate P450 genes have been identified and
sequenced. They comprise 17 families of oxidative en-
zymes with >40% sequence homology at the protein level;
subfamilies are further defined by >70% homology. P450
enzymes are identified numerically by family, alphabet-
ically by subfamily, and individually by number, e.g.
CYP3A4 [32]. Many analgesic and psychoactive drugs are
metabolized by one of three P450 enzymes. The major
cytochrome in humans is 3A4, which is involved in 50% of
all microsomal drug metabolism, and is responsible for the
metabolism of methadone, fentanyl, and certain selective
serotonin reuptake inhibitors [32, 36]. Of importance for
clinical therapeutics, all cytochrome P450 enzymes other
than 2D6 are inducible [37].
Morphine
Morphine is glucuronidated by the hepatic enzyme UDP-
glucuronyl transferase and produces two major metabolites,
morphine-6-glucuronide (M6G) and morphine-3-glucuro-
nide (M3G), both of which are excreted in the urine [38].
M6G is a highly potent analgesic opioid that activates the
μ-receptor and is inactive in MOR-deficient mice [38, 31].
M3G, the predominant metabolite of morphine, has no
opioid properties and has been proposed to be responsible
for neuroexcitatory effects, including allodynia, myoclo-
nus, and seizures, that may accompany large doses of
morphine [39, 40]. The results of a study [41] cast doubt
on this hypothesis by demonstrating that renal failure
invariably leads to elevated concentrations of both metab-
olites, often resulting in respiratory depression, obtunda-
tion, and central nervous system (CNS) hyperexcitability,
and showing that M3G lacks pharmacologic activity in
humans [1, 41].
Metabolite
Morphine-3-glucuronide
Morphine 6-glucuronide
Morphine
Oxymorphone
Noroxycodone, α and β oxycodol
Inactive metabolites
Inactive metabolites
Morphine
Norpropoxyphene
Normeperidine
Codeine
CYP2D6 catalyzes the demethylation of codeine to the
more active metabolite morphine. Extensive metabolizers
convert 6% to 9% of administered codeine to morphine,
compared with only a trace in poor metabolizers. Con-
sequently, an analgesic response to codeine occurs in ex-
tensive metabolizers only, even though both groups are
responsive to the effects of morphine itself. Furthermore,
the adverse effects of codeine unrelated to its conversion
to morphine are observed in both genotypes; poor me-
tabolizers, therefore, experience the side effects, but not
the analgesic effects, of codeine [42].
Meperidine
The clinical consequences of opioid metabolism may also
impact medical practice. The synthetic opioid meperidine
had been a widely used analgesic routinely prescribed for
moderate-to-severe pain in medical and surgical patients.
However, its metabolic product, normeperidine, produces
CNS hyperexcitability presenting as adverse effects rang-
ing from nervousness to tremors, twitches, multifocal
myoclonus, and grand mal seizures. Although excreted
by the kidneys, the accumulation of normeperidine may
lead to neurologic toxicity even with normal renal func-
tion [1, 43]. The association with CNS toxicity was not
noted earlier because meperidine had been traditionally
prescribed at subtherapeutic doses. Recognition of the
adverse effect of this metabolite has led to the current
recommendation that the use of meperidine be limited only
to patients allergic to or otherwise unable to tolerate all
other opioids [44, 45]. Meperidine also has a potential
lethal interaction with monoamine oxidase inhibitors [46].

Agonist-antagonist combinations
Opioid antagonists are molecules that block or reverse the
pharmacologic effects of opioid agonists by competing for
opioid receptor sites. Unlike agonist binding, which leads
to decreased neurotransmitter release and impulse propa-
gation, antagonist binding does not result in the usual in-
tracellular responses brought about by inhibitory G-protein
(Gi/Go) activation. The antagonist naloxone has a binding
affinity for the μ-receptor that is similar to that of
morphine (Table 1) [18]. Experimentally, however, low
concentrations of naloxone have been shown, paradoxi-
cally, to induce analgesia in mice by blocking the pre-
synaptic autoinhibition of enkephalin release thus causing
an exaggerated release of endogenous opioids [47, 48].
Recent in vitro and in vivo data from animals have
demonstrated that extremely low doses of the opioid
antagonist naltrexone can enhance the antinociceptive
effects of morphine and other opioid agonists, allowing
such agents to be administered at far lower doses than
those normally required for analgesia. The basis for these
observations is a bimodal effect of opioid agonists. At
extremely low doses, morphine can produce hyperalgesia
to painful stimuli in mice, whereas at normal doses, typical
analgesic effects are elicited [49]. An ultra-low dose of an
opioid antagonist appears to block only the hyperalgesic
effect, unmasking the analgesic effect of the low-dose
agonist. At higher doses, antagonists block both excitatory
and inhibitory activities. It has been suggested that no-
ciceptive neurons contain small numbers of excitatory GS-
protein-coupled opioid receptors responsible for adverse
opioid effects, in addition to the more abundant inhibitory
Gi/Go-protein-coupled receptors responsible for initiating
the ordinary antinociceptive response [49]. In neuronal
cell culture, the opioid antagonist naloxone selectively
blocks excitatory GS-coupled responses elicited by very
low concentrations of morphine and unmasks the analge-
sic inhibitory Gi/Go-coupled effects of these low opioid
concentrations [49, 50].
It has been proposed that coadministration of an ultra-
low dose of naloxone or naltrexone may allow the clinical
use of morphine doses that are low enough to reduce
tolerance, dependence, and other adverse effects [49].
Several clinical trials of low-dose opioid antagonists
coadministered with morphine have suggested that this
approach might reduce morphine requirements and side
effects associated with morphine administration, including
respiratory depression, urinary retention, nausea, vomit-
ing, and pruritus in patients requiring pain management
[51, 52]. In one randomized, placebo-controlled study,
patients undergoing total abdominal hysterectomy who
were treated with morphine via patient-controlled analge-
sia (PCA) plus naloxone (0.25 μg/kg per hour) adminis-
tered as a continuous intravenous infusion experienced an
approximately 30% decrease in cumulative morphine use
compared with morphine plus placebo-treated patients in
157
the first 24 h after surgery [53]. However, in a second trial
of general surgical patients, treatment with low-dose
naloxone (average dose 0.5 μg/kg per hour for the first
2 h; 0.06 μg/kg per hour from hours 2 to 24 of ob-
servation) plus morphine via PCA-administered intermit-
tent boluses resulted in higher morphine requirements,
greater pain intensity, and less pain relief and satisfaction
than treatment with morphine plus placebo [54].
Unfortunately, differences in naloxone and morphine
dosages and modes of administration do not allow a direct
comparison of the contradictory findings from these two
trials. Low naloxone doses above a certain critical level
still appear to allow opioid antagonism to predominate,
whereas ultra-low doses may be necessary for the desired
proanalgesic effect. Also, synergism was apparent only at
lower, but not at higher, morphine doses. Furthermore, an
intermittent bolus may precipitate a period of hyperalgesia
due to higher initial naloxone levels, followed by a period
of excitatory opioid receptor sensitization by opioid ex-
posure [55]. At present, evidence for the use of low-dose
antagonism is contradictory, and the routine introduction of
this approach into clinical practice remains controversial.
Conclusions
The opioid alkaloids are potent clinical analgesics the use
of which can be accompanied by significant adverse
effects, including respiratory depression, nausea, vomit-
ing, pruritus, and neuroexcitation. Use of these agents
is also associated with mood elevation, tolerance, and
dependency. However, the rate of development of tol-
erance between patients is highly variable and opioid
dependency is not considered a major clinical problem in
appropriately selected patients. Opioid action is mediated
through high-affinity G-coupled receptors that produce
inhibition of the nociception pathways. Three receptor
types—μ, δ, and κ—have been defined pharmacologically
and their respective genes have been cloned. Several sub-
types of each receptor have been proposed on the basis
of differential pharmacologic effects; although no sepa-
rate genes have been identified, evidence for alternatively
spliced variants has been presented.
Many opioid analgesics, including codeine, fentanyl,
and methadone, are metabolized by hepatic cytochrome
P450 enzymes, mainly 3A4 and 2D6. The presence of
polymorphisms in CYP2D6 defines poor versus extensive
metabolizers. Poor metabolizers do not obtain analgesic
relief from codeine, which must be transformed to
morphine, but they do experience adverse effects. Mor-
phine is metabolized through glucuronidation into the
active analgesic M6G and the inactive metabolite M3G,
and accumulation of these metabolites may actually induce
neuroexcitability. Renal failure may lead to accumulation
of both metabolites, thus resulting in combined toxicities.
158

Growing pharmacologic and molecular understanding
of the opioid system may bring the development of novel
opioids that may reduce the adverse effects that occasion-
ally result from opioid treatment. One strategy, which has
experimental support, suggests that morphine doses can be
lowered by the coadministration of an ultra-low dose of an
opioid antagonist such as naloxone; however, there are
conflicting clinical results on the efficacy of this combined
therapy, and additional trials in humans are warranted.
Acknowledgements The preparation of this article was supported
by Endo Pharmaceuticals, Chadds Ford, Pennsylvania, with editorial
assistance provided by Accel Medical Education, New York, New
York.

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