Download Treatment of opioid-induced gut dysfunction

Review
Central & Peripheral Nervous Systems
Treatment of opioid-induced gut
dysfunction
Peter Holzer
1. Introduction
Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical
Pharmacology, Medical University of Graz, Universitätsplatz 4, A-8010 Graz, Austria
2. Opioid peptides and opioid
receptors in the gastrointestinal
3. Opioid actions in the
ly
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gastrointestinal tract
4. Significance of endogenous
opioid peptides in
gastointestinal physiology
5. Homeostatic roles of
dysfunction
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receptor stimulants under
7. Adverse effects of opioid
receptor agonists on gut
function: opioid-induced bowel
dysfunction and prolongation
of postoperative ileus
8. Treatment of opioid-induced
1. Introduction
disturbances of bowel function
and related substances contained in the unripe seed capsules of
. Morphine
Papaver somniferum have been used to treat pain and diarrhoea for thousands of
with laxatives and non-opioid
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9. Management of opioid-induced
receptor antagonists with a
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peripherally restricted site of
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10. Opioid receptor antagonists
with a peripherally restricted
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site of action as possible
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prokinetic drugs
11. Expert opinion
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Keywords: alvimopan, constipation,
a enteric nervous system, intestinal peristalsis, naloxone,
N-methylnaltrexone, opioid
peptides, opioid-induced bowel dysfunction, peripherally restricted
g
opioid receptor antagonists,
in prokinetic effects
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in Drugs (2007) 16(2):181-194
Expert Opin. Investig.
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conditions of gut dysfunction
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6. Beneficial effects of opioid
bowel dysfunction by opioid
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endogenous opioids in gut
prokinetic drugs
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Opioid analgesics are the mainstay in the treatment of moderate-to-severe
pain, yet their use is frequently associated with adverse effects, the most
common and debilitating being constipation. Opioid-induced motor stasis
results from blockade of gastrointestinal peristalsis and fluid secretion, and
reflects the action of the endogenous opioid system in the gut. Methylnaltrexone and alvimopan are new investigational drugs that selectively target peripheral µ-opioid receptors because they are poorly absorbed in the
intestine and do not enter the brain. Clinical studies have proved the concept
that these drugs prevent opioid-induced bowel dysfunction without interfering with analgesia. As reviewed in this article, opioid receptor antagonists
with a peripherally restricted site of action also hold therapeutic promise in
postoperative ileus and chronic constipation due to the fact that they have
been found to stimulate intestinal transit.
tract
years. At present, opioid analgesics are the mainstay of therapy in many patients
with moderate-to-severe pain. Unfortunately, adverse effects can severely compromise the therapeutic benefit offered by these drugs [1]. The gastrointestinal (GI)
tract is one of the main targets of their unwanted actions and, in this property,
opioid analgesics are similar to other neuroactive drugs, notably adrenoceptor agonists [2-4]. This pharmacological profile reflects the significant role that neurons play
in GI function and the fact that many of the transmitters and transmitter receptors
present in the brain have also been localised to the gut. This is particularly true for
opioid receptors and adrenoceptors whose activation by opiates and catecholamines,
respectively, interferes with pathways of the enteric nervous system that regulate
motility and secretion [1-9].
To comprehend the adverse actions of opioid analgesics and other neuroactive
drugs on the gut, it needs to be considered that the alimentary canal is equipped
with the largest collection of neurons outside the CNS. Enteric neurons originating
from the myenteric and submucosal plexuses supply all of the layers of the
alimentary canal and, therefore, are in a position to regulate virtually every aspect of
digestion [10-12]. These neurons not only synthesise and release acetylcholine, substance P, NO, ATP, vasoactive intestinal polypeptide and 5-HT but also opioid peptides as their transmitters. The enteric nervous system is arranged in polarised
circuits that are typically composed of intrinsic primary afferent neurons, a variable
number of interneurons and excitatory or inhibitory output (motor, secretomotor
and vasodilator) neurons to the effector tissues [10-12]. With this organisation, the
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Treatment of opioid-induced gut dysfunction
enteric nervous system is capable of regulating GI peristalsis,
ion and fluid secretion, circulation, endocrine and immune
activity independently of the brain [10-12].
2. Opioid
peptides and opioid receptors in the
gastrointestinal tract
The adverse influence of opioid analgesics on GI function
remained an enigma to scientists until it was realised that both
opioid peptides and opioid receptors are expressed in the
digestive tract; therefore, it is important to briefly consider the
endogenous opioid system in the gut and its physiological and
pathophysiological implications (Figure 1) to understand the
basis of opioid-induced bowel dysfunction (OBD).
Met-enkephalin, leu-enkephalin, β-endorphin and dynorphin
are among the endogenous opioids that are present in the GI
tract where they have been localised to both neurons and
endocrine cells of the mucosa [1,5,13]. Neuroanatomical tracing
studies have revealed that opioid peptides are present in distinct classes of enteric neurons in the guinea-pig, notably in
myenteric neurons projecting to the circular muscle and in
neurons of descending enteric pathways [13-15].
The presence of endogenous opioids in the alimentary
canal is matched by the expression of opioid receptors that
mediate the effect of both endogenous and exogenous opioid
receptor ligands on bowel function. By using mRNA quantification and immunocytochemistry, opioid receptors of the µ-,
κ- and δ-subtype have been localised to the GI tract of rats,
guinea-pigs and humans [13,16-18]. In the rat and guinea-pig,
all three subtypes of opioid receptors are found on neurons of
the myenteric and submucosal plexuses and on nerve fibres
supplying muscularis and mucosa; however, their relative distribution varies with GI layer, GI region and species [13]. In
the human gut, µ-opioid receptors are present on myenteric
and submucosal neurons and on immune cells of the lamina
propria [13].
animals; however, analysis of the cellular mechanisms of opiate action has shown that opioid receptor agonists can interrupt both excitatory and inhibitory neural inputs to the GI
muscle in both human and animal models [21].
Inhibition of excitatory neural inputs is associated with
inhibition of the release of excitatory transmitters such as
acetylcholine and blockade of distension-induced peristaltic contractions, whereas blockade of inhibitory neural
inputs results in depression of NO release from inhibitory
motor neurons, disinhibition of GI muscle activity, elevation of resting muscle tone and non-propulsive motility
patterns [6,8,13,21,23,24]. A direct activation of the interstitial
cell–muscle network has also been envisaged [25,26]. In the
canine gut, µ-opioid receptor agonists have a biphasic excitatory and inhibitory influence on the migrating myoelectrical complex [27], and transit in the human colon is
retarded by activation of µ-opioid (but not κ-opioid)
receptors [28,29]. Other studies have shown that activation of
µ-opioid receptors in the human gut can increase pyloric
tone, induce pyloric (as well as duodenojejunal phasic)
pressure activity and elevate the resting anal sphincter pressure [30,31]. The relative contribution of these multiple
effects to opioid-induced constipation is not clear [7].
Apart from affecting GI motor activity, opioids also influence GI ion and fluid transport (Figure 1). Blunted peristalsis
delays GI transit and, thereby, prolongs the contact of the
intestinal contents with the mucosa [1]. As a result, absorption
of fluid is increased, whereas the secretion of electrolytes and
water is decreased in the small and large intestines [6,21,32,33].
The antisecretory effect of opiates is mediated by opioid
receptors on enteric neurons, whose activation results in the
interruption of prosecretory enteric reflexes [6,21].
The actions of endogenous opioids on the GI tract are
mediated by multiple opioid receptors. Studies with isolated
tissues from the human intestine suggest that δ-, κ- and
µ-opioid receptors contribute to opiate-induced inhibition of
muscle activity [34,35]. Propulsion in the rat intestine is
blocked by δ- and µ- (but not κ-) opioid receptor agonists [6],
whereas peristalsis in the guinea-pig intestine is suppressed by
activation of κ- and µ- (but not δ-) opioid receptors [20]. Opiate-induced inhibition of cholinergic transmission in the
guinea-pig gut is similarly mediated by µ- and κ-opioid
receptors [36].
Opioid receptors belong to the family of metabotropic
membrane receptors that couple via the Gi/Go subtypes of
G proteins to cellular transduction processes. Once activated
by an agonist, µ-opioid receptors undergo endocytosis in a
concentration-dependent manner [13,16,21]. The cellular effects
of myenteric µ-opioid receptor activation are instigated by a
multiplicity of signalling pathways including activation of K+
channels, membrane hyperpolarisation, inhibition of Ca2+
channels and reduced production of cAMP [21,36].
Taken together, opioid-induced constipation results from
multiple effects, such as suppression of enteric neuron
excitability, inhibition of excitatory and inhibitory neural
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3. Opioid actions in the
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When released fromI enteric neurons, it is likely that opioid
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peptides play a o
mediator role in the regulation of propulsion
and secretiont
. This conjecture is reflected by the
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actions iof
exogenous opioid receptor agonists and antagonists
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GIr function (Figure 1). The inhibitory effect of opioid
receptor
p agonists on peristalsis in the guinea-pig small inteso
tine is thought to arise primarily from the interruption of
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[2,5,6,8,9,19-21]
transmission within enteric nerve pathways governing muscle
activity [13,21,22]. Transmission can be blocked both via presynaptic and postsynaptic sites of action on enteric neurons,
whereby the release of acetylcholine and other transmitters is
attenuated [6,21]. It has previously been believed that opiates
inhibit GI propulsion in some species such as the guinea-pig
by suppression of peristaltic contractions, whereas GI propulsion is interrupted through induction of non-propulsive
contractions in the intestine of humans and non-rodent
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Gastrointestinal actions
Cellular sources
Met-enkephalin
Leu-enkephalin
β-Endorphin
Dynorphin
Enteric neurons
• Neurons of the myenteric plexus with
projections within the plexus to the circular
muscle and to the mucosal plexus
• Neurons of the submucosal plexus
Endocrine cells
Inhibition of enteric nerve activity
• Suppression of enteric nerve excitability
• Pre- and postsynaptic inhibition of
transmission in excitatory and inhibitory
motor as well as secretomotor pathways
• Inhibition of the release of acetylcholine,
substance P and NO
Inhibition of propulsive motor activity
• Inhibition of distension-induced peristalsis
• Elevation of muscle tone
• Induction of non-propulsive motility patterns
• Disturbance of migrating myoelectrical
complex
• Inhibition of gastric emptying
• Delay of gastrointestinal transit
• Constipation
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Molecular/cellular targets
µ-Opioid receptors
κ-Opioid receptors
δ-Opioid receptors
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Inhibition of secretory activity
• Inhibition of ion and fluid secretion
• Constipation
Enteric neurons (somata and axons)
Immune cells
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Immune activity
• Alteration of immune cell function
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a gastrointestinal tract.
Figure 1. Schematic summary of the endogenous opioid system in the
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inputs to the GI muscle and mucosa, inhibition of propulin It follows that the endogenous opioid peptides that are
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in the course of propulsive motility
sion, induction of non-propulsive motility patterns
participate
P and inreleased
depression of secretory activity (Figure 1) . Although there
the neural control of peristalsis as they dampen peri[37]
[21]
are species differences in the GI distribution of opioid receptors in the gut and the GI effect profile of opiates, emerging
evidence indicates that the principal opioid actions on the
enteric nervous system are seen in all mammalian species,
although to a different degree depending on the experimental
conditions. As a systematic comparison of opioid peptide
occurrence, opioid receptor distribution and opioid effect
profile in the gut of various species has not been performed,
the true extent of species differences and the most appropriate
animal model for OBD remain uncovered.
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4. Significance
of endogenous opioid peptides
in gastointestinal physiology
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There is evidence for a role of endogenous opioid peptides
in the fine-tuning of gut functions. This concept is primarily based on the ability of opioid receptor antagonists
to influence GI physiology and pathophysiology; for example, distension-evoked peristalsis can be facilitated by the
pan-opioid receptor antagonist naloxone in various preparations of the guinea-pig, rabbit, cat and rat isolated
small intestine [6,8,19,20]. In the guinea-pig small intestine,
the effect of naloxone is mimicked by selective antagonists
at µ- (cyprodime) and κ- (norbinaltorphimine) opioid
receptors, but not by antagonism at δ-opioid receptors [20].
staltic performance via activation of µ- and κ-opioid receptors [20]. This inference is further supported by the ability
of µ- and κ-opioid receptor antagonists to enhance the
release of acetylcholine from the guinea-pig myenteric
plexus [38]; by the ability of methylnaltrexone to enhance
neurogenic contractions in the isolated human small intestine [39]; and by the ability of naloxone to increase the
release of substance P from the peristaltically active
guinea-pig ileum [37]. Naloxone has been found to accelerate transit in the colon but not the small intestine of
healthy human volunteers [28,40]. This prokinetic effect is
shared by the µ-opioid receptor-preferring antagonists
methylnaltrexone [41] and alvimopan [42].
5. Homeostatic
roles of endogenous opioids in
gut dysfunction
Schaumann [43] interpreted the pharmacological effects of
exogenous opiates on pain and bowel function as indicative of
an endogenous protective system a long time before endogenous opioid peptides were identified [44]. Backed by increasing experimental support, it is now thought that endogenous
opioids in the GI tract represent a system that defends the
intestine against functional derangements created by
inappropriate or adverse conditions such as prolonged
Expert Opin. Investig. Drugs (2007) 16(2)
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Treatment of opioid-induced gut dysfunction
intestinal distension, inflammation, stress and trauma [8,9]; for
example, prolonged intraluminal distension of the guinea-pig
ileum causes peristaltic activity that is interrupted by periods
of inactivity during which the release of met-enkephalin is
significantly enhanced [45]. This observation is consistent with
the ability of naloxone to reduce the intermittent periods of
peristaltic inactivity observed during prolonged periods of
distension [46-48]. Studies of the effects of naloxone in rats suggest that endogenous opioids contribute to the ileal brake of
the stomach-to-caecum transit caused by ileal infusion of
lipids [49].
Disruption of the migrating myoelectrical complex caused
by the administration of Escherichia coli endotoxin to fasted
rats is reduced by naloxone [50]. This opioid receptor antagonist has no effect on the delay in rat GI transit (measured with
a liquid dye marker) that is caused by abdominal skin incision
or abdominal laparotomy but inhibits the delay in transit
measured after abdominal laparotomy plus manipulation of
the small and large intestines [51]. Furthermore, naloxone and
methylnaloxone minimise the increase in rat colonic epithelial
ion secretion and permeability that was observed after
prolonged periods of stress [52].
There is increasing evidence that GI pathophysiology
leading to gut motor inhibition is associated with
upregulation and/or overactivity of the opioid system in the
alimentary canal; for example, experimental inflammation
enhances the potency of µ-opioid receptor agonists to
inhibit GI transit and to increase the transcription and
expression of µ-opioid receptors in the intestine of
mice [53,54]. Abdominal surgery leads to an increase in the
circulating levels of endomorphin in humans [55] and causes
a profound internalisation of µ-opioid receptors in the
myenteric plexus of the guinea-pig intestine [13], observations that may reflect a role of endogenous opioids in the
pathophysiology of postoperative motor disturbances; therefore, it is emerging that endogenous opioids play a more
important role in the pathological than in the physiological
inhibition of gut motility [2,8]. Consistent with this concept
is a limited number of small studies showing that naloxone
can reverse idiopathic chronic constipation [56] and can have
beneficial activity in patients with intestinal pseudo-obstruction [57] and constipation-predominant irritable bowel syndrome [58]; however, these studies need to be confirmed by
larger controlled trials involving opioid receptor antagonists
that have a more favourable pharmacokinetic profile than
the short-lived naloxone to prove the concept.
The effect of naloxone to normalise pathologically deranged
GI motor activity is consistent with its ability to rescue peristalsis from experimentally induced inhibition. Thus, opioid
receptor antagonism does not affect propulsion in the
guinea-pig isolated colon under normal conditions but attenuates the inhibition of faecal pellet transport caused by granisetron, morphine or clonidine [59]. Similarly, naloxone is capable
of reversing the inhibition of peristalsis in the guinea-pig small
intestine caused by purinoceptor ligands, haloperidol,
noradrenaline, atropine or hexamethonium [19,46,60,61]. With
all of these findings together, it follows that endogenous
opioids contribute to GI homeostasis, particularly under
conditions of disturbed gut function.
6. Beneficial
effects of opioid receptor
stimulants under conditions of gut
dysfunction
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7. Adverse
effects of opioid receptor agonists
on gut function: opioid-induced bowel
dysfunction and prolongation of
postoperative ileus
There are two key GI syndromes associated with the use of
opioid analgesics: OBD and postoperative ileus in which opiates are one of many factors contributing to prolonged GI
motor stasis [1,7].
A delay in GI transit and constipation are the most common and often disabling side effects of opioid analgesics,
which result from their spectrum of pharmacological actions
to block propulsive peristalsis, inhibit intestinal ion and
fluid secretion, and increase intestinal fluid absorption [6];
however, constipation is just one symptom of OBD, whose
manifestations comprise incomplete evacuation, abdominal
distension, bloating, abdominal discomfort and increased
gastro- oesophageal reflux. In addition, OBD may lead to
secondary complications such as pseudo-obstruction of the
bowel, anorexia, nausea and vomiting as well as interference
with oral drug administration and absorption [1,7,67]. The
symptoms associated with OBD can profoundly impair the
quality of life and (in some patients) can be so severe that
they prefer to discontinue analgesic therapy rather than
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The actions of opioid receptor agonists to inhibit GI secretory
activity and transit are therapeutically used in acute and
chronic diarrhoea as well as in irritable bowel syndrome associated with diarrhoea [7]. Inhibition of diarrhoea is achieved
by two strategies. The first strategy is to target opioid receptors in the gut, a possibility that has long been accomplished
by the development of loperamide. The antidiarrhoeal action
of this compound is predominantly mediated by µ-opioid
receptors and is restricted to the gut because loperamide is
poorly absorbed and fails to cross the blood–brain barrier at
concentrations needed to produce analgesia [6,30,62]. The second strategy is to inhibit enkephalinases that degrade endogenous opioids once they have been released from neurons or
other cells in the GI tract. Inhibition of GI enkephalinases by
racecadotril (acetorphan, a compound that does not enter the
brain) prolongs the presence – and increases the concentration
– of endogenous opioid peptides at opioid receptors in the alimentary canal [63,64]. In this way, the antisecretory and antitransit effects of endogenous opioid peptides are enforced, a
result that is therapeutically used for the treatment of
diarrhoea [65,66].
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experience the discomfort arising from OBD [1,67]. Unlike
other adverse effects of chronic opioid therapy such as sedation, nausea and vomiting, which often resolve with continued use, OBD generally persists throughout treatment [1,68];
however, tolerance to the effects of morphine on enteric
neurons has been found to occur in animal experiments
in vitro [21].
Although centrally mediated effects of opiates to slow GI
transit have been implicated in the pathophysiology of
OBD [62], opiate-induced blockade of gut motility correlates
better with opiate concentrations in the gut than with opiate
concentrations in the brain [67,69]. In addition, the N-methyl
quaternary analogues of naloxone and naltrexone (which do
not cross the blood–brain barrier) have been found to fully
antagonise the effects of morphine on opioid-induced
effects in the canine and rat intestines [70,71]; therefore, it
would seem that the adverse effects of opiates on GI function result primarily from interaction with opioid receptors
in the gut [1,62].
Postoperative ileus occurs most commonly following
abdominal or pelvic surgery and is characterised by bowel distension, lack of bowel sounds, accumulation of GI gas and
fluid, nausea, vomiting and delayed passage of flatus and
stool [1,4,7]. Motor stasis involves all segments of the digestive
tract, the colon being most severely affected because the
average paralytic state in this part of the intestine persists for
48 – 72 h [1]. Opioid analgesics have a profound inhibitory
effect on postoperative GI motility and their use for postoperative analgesia delays recovery from postoperative ileus.
There is a significant relationship between the amount of
morphine administered and time required for resolution of
ileus following colectomy [72]. The inhibitory effects of opioid
analgesics on postoperative GI motility are observed during
systemic opioid administration with patient-controlled
analgesia and conventional intramuscular as well as epidural
opioid administration [1]. As the pathophysiology of prolonged postoperative ileus involves inflammatory, immunological and neurogenic mechanisms [73,74], it should not be
neglected that the effects of opioid analgesics on the immune
system may be of relevance to their adverse influence on
postoperative ileus [7].
postoperative ileus include metoclopramide, domperidone
and erythromycin to stimulate primarily foregut motility;
the cholecystokinin (CCK) analogue caerulein to stimulate
small intestinal motility; acetylcholinesterase inhibitors such
as neostigmine to enforce small and large intestinal tone;
and the 5-HT4 receptor agonist tegaserod to stimulate
colonic transit [1,4,76]. Erythromycin-related motilides, ghrelin analogues, the mixed 5-HT4 receptor agonist/5-HT3
receptor antagonist renzapride and the CCK1 receptor
antagonist dexloxiglumide represent further prokinetic drug
candidates that are in clinical development [4,76]; however,
the therapeutic value of prokinetic drugs in the relief of
postoperative ileus with or without opiate use remains
unsubstantiated [1]. It seems that epidural local anaesthesia
(among all of the available pharmacological treatment
options) is the most effective method for relieving pain and
shortening the duration of ileus [1].
Similarly, prokinetic drugs are used to ameliorate
OBD, although laxatives are most commonly used in this situation [1,67,75]; however, these regimens often do not provide
satisfactory relief from the GI manifestations of
opioid-induced analgesia [1].
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prokinetic drugs
The pharmacological treatment of OBD and postoperative
ileus associated with opiate use involves two approaches:
non-specific treatment with laxatives and prokinetic drugs;
and specific treatment with opioid receptor antagonists. As
this review focuses on the second approach, the first
approach involving non-opioid drugs is only briefly
addressed. Laxative drugs (including softening, stimulant
and osmotic laxatives) have long been used to ameliorate
OBD [1,67,75]. The prokinetic treatment options for
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9. Management
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The primary objective in the management of OBD
(whether or not associated with postoperative ileus) is to
prevent GI symptoms rather than treat established motor
stasis due to opioid use [1]. For this reason, many
opioid-sparing regimens (e.g., NSAIDs and tramadol) have
been tested to circumvent the adverse GI sequelae of opioid
use [1]; however, these regimens may lack efficacy in severe
pain states or may themselves have adverse effects on the
gut. Although transdermal administration of opiates such as
fentanyl causes less constipation and results in a better
quality-of-life rating than oral administration of
morphine [1,77,78], this approach also represents only a
partial solution of the problem.
Given that opioid-induced analgesia is primarily mediated
by µ-opioid receptors in the CNS, the rational approach to
prevent OBD would be to combine opioid analgesics with
opioid receptor antagonists that cannot penetrate the
blood–brain barrier. As a result, the adverse effects of opioid
analgesics on the GI system would be avoided, whereas their
central analgesic action would remain unaltered. This
approach has been validated by the use of opioid receptor
antagonists with limited systemic absorption and by the
development of peripherally restricted opioid receptor
antagonists (PRORAs) such as methylnaltrexone and alvimopan. The latter two compounds are presently in clinical
trials for the management of OBD and postoperative ileus
(Table 1) and may also turn out to become prokinetic drugs
to relieve intestinal stasis unrelated to opiate use.
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Treatment of opioid-induced gut dysfunction
Table 1. Overview of fully published clinical trials of methylnaltrexone and alvimopan in OBD and postoperative
ileus.
Ref.
Compound and dose
Trial type Major outcome
[41]
Methylnaltrexone 0.3 mg/kg i.v. every 6 h Phase I
Safety, pharmacokinetics and efficacy of methylnaltrexone to stimulate
GI transit
[85]
Methylnaltrexone 0.64, 0.7, 2.1, 6.4 or
19.2 mg/kg p.o.
Phase I
Safety and efficacy of methylnaltrexone to prevent OBD
[86]
Methylnaltrexone 0.45 mg/kg i.v.
Phase I
Safety and efficacy of methylnaltrexone to prevent OBD
[88]
Methylnaltrexone 0.04, 0.08, 0.16, 0.32,
0.64 or 1.25 mg/kg i.v.
Phase I
Safety and pharmacokinetics of methylnaltrexone
[89]
Methylnaltrexone 0.3 mg/kg i.v.
Phase I
Efficacy of methylnaltrexone to ameliorate morphine-induced delay of
gastric emptying
[90]
Methylnaltrexone 0.1 or 0.3 mg/kg s.c.
Phase I
[91]
Methylnaltrexone 3.2 or 6.4 mg/kg p.o.
Phase I
[92]
Methylnaltrexone 0.1 mg/kg/day i.v.
Phase II
[93]
Methylnaltrexone 0.3 or 1 mg/kg p.o.
Phase II
[42]
Alvimopan 12 mg b.i.d. p.o.
Phase I
[99]
Alvimopan 4 mg p.o.
Phase I
[100]
Alvimopan 0.5 or 1 mg q.d. p.o.
Phase II
[101]
Alvimopan 1 or 6 mg b.i.d. p.o.*
Phase II
[102]
Alvimopan 6 or 12 mg b.i.d. p.o.*
Phase III
[103]
Alvimopan 6 or 12 mg b.i.d. p.o.*
Phase III
[104]
Alvimopan 12 mg b.i.d. p.o.*
Phase III
[105]
Alvimopan 6 or 12 mg b.i.d. p.o.*
Phase III
*The initial dose of alvimopan was given 2 h before surgery.
GI: Gastrointestinal; OBD: Opioid-induced bowel dysfunction.
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The first attempt to selectively target opioid receptors in the
periphery was made with naloxone and related tertiary opioid
receptor antagonists such as nalmefene [1]. Naloxone is a
pan-opioid receptor antagonist [79] whose systemic bioavailability following oral administration is as low as 2%
because of extensive first-pass metabolism. For this reason,
oral naloxone has been found to improve OBD without
inhibiting opiate-induced analgesia [80-82]. However, it needs
to be realised that naloxone can easily cross the blood–brain
barrier; therefore, naloxone can reverse analgesia if given in
sufficient dosage despite its low bioavailability [1]. Consequently, the therapeutic index of naloxone has turned out to
be very narrow and its use limited because of the need to
titrate active doses peripherally versus centrally [81].
Nalmefene is a µ-opioid receptor antagonist and its
metabolite (nalmefene glucuronide) has been observed to
selectively antagonise the GI effects of opioid analgesics in
rodents; however, nalmefene glucuronide does not seem to be
sufficiently selective for the gut to be clinically useful in
humans [83].
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Pharmacokinetics and efficacy of methylnaltrexone to ameliorate
ic OBD
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Pharmacokinetics and efficacy of methylnaltrexone to ameliorate OBD
s
Safety and efficacy of methylnaltrexone to ameliorate
OBD due to
n
chronic methadone
it o
Safety and efficacy of methylnaltrexone to
uameliorate OBD due to
b
chronic methadone
i
trstimulate GI transit and prevent OBD
Safety and efficacy of alvimopansto
Efficacy of alvimopan to prevent
di OBD
d to ameliorate OBD
Safety and efficacy of alvimopan
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Efficacy of alvimopan
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Safety and efficacy
n of alvimopan to shorten postoperative ileus
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Safety and
n efficacy of alvimopan to shorten postoperative ileus
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Safety and efficacy of alvimopan to shorten postoperative ileus
P
Safety and efficacy of alvimopan to shorten postoperative ileus
9.1 Opioid receptor antagonists with limited systemic
absorption
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9.2 Methylnaltrexone
An important advance in the search for PRORAs was the
development of quarternary opioid receptor antagonists
such as methylnaltrexone. Attaching a methyl group to the
amine configuration in naltrexone results in methylnaltrexone (Figure 2), a drug that has greater polarity and
lower lipid solubility than its parent compound [84]. Due to
its quaternary structure, methylnaltrexone exhibits low oral
bioavailability due to limited absorption and does not cross
the blood–brain barrier [67,84,85]. As a result, this µ-opioid
receptor-preferring antagonist (MIC = 70 nM) offers the
therapeutic potential of preventing or reversing the
undesired side effects of opioids in the gut without compromising analgesia or precipitating the opioid withdrawal
symptoms that are predominantly mediated by opioid receptors in the brain [84]. Early studies have revealed that the
adverse effect of the opiate on GI function is prevented
without attenuation of analgesia following subcutaneous or
intravenous administration of methylnaltrexone together
with a centrally active opiate to dogs and humans [67,86],
whereas analgesia is appreciably compromised in rats [70].
This species dependence of the peripheral selectivity of
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Methylnaltrexone
Intravenous administration in healthy volunteers
No adverse effects of clinical importance with
methylnaltrexone ≤ 0.45 mg/kg [41,86]
Orthostatic hypotension and lightheadedness following
administration of methylnaltrexone 0.64 or 1.25 mg/kg at
plasma levels in excess of 1.4 µg/ml [88]
HO
O
HO
Box 1. Significant adverse effects of
methylnaltrexone and alvimopan relative to
placebo.
O
Naltrexone
Figure 2. Chemical
methylnaltrexone.
O
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Methylnaltrexone
structures
of
naltrexone
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Subcutaneous administration in healthy volunteers
No adverse effects of clinical importance with
methylnaltrexone ≤ 0.3 mg/kg [90]
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Oral administration in healthy volunteers
No adverse effects of clinical importance with
methylnaltrexone ≤ 19.2 mg/kg [85]
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Intravenous administration in methadone-maintained
subjects
Mild-to-moderate abdominal cramping following
administration of methylnaltrexone 0.1 mg/kg [92]
and
methylnaltrexone arises from its demethylation to naltrexone, which readily penetrates the blood–brain barrier:
demethylation occurs in mice and rats but is negligible in
dogs and humans [87].
A substantial series of Phase I and II studies conducted by
the group of Yuan [84] has established the pharmacodynamic,
pharmacokinetic, therapeutic and safety profiles of
methylnaltrexone [84]. The drug has been formulated as a
solution for intravenous or subcutaneous administration as
well as capsules/tablets for oral administration [84]. Both the
parenteral and oral formulations as well as single- and
repeated-dose regimens have been found to be effective in preventing the morphine-induced prolongation of gastric emptying and oral-to-caecal transit time without significantly
attenuating morphine-induced analgesia (Table 1) [41,85-90].
Following injection of methylnaltrexone 0.3 – 0.45 mg/kg
i.v., the time to maximum plasma concentration is ∼ 20 min,
the elimination half-life in plasma is ∼ 1.5 – 3 h and the terminal half-life is ∼ 6 – 9 h [84]. Repeated administration of
0.3 mg/kg i.v. at 6-h intervals does not result in an accumulation of the drug [41] and the available data indicate that the
metabolism of methylnaltrexone does not play a major role in
its predominantly renal route of elimination [84].
Although readily bioavailable following parenteral administration, methylnaltrexone is absorbed from the GI tract only
to a limited extent [85]. The plasma levels of methylnaltrexone
are even lower when the drug is administered orally as an
enteric-coated formulation, yet enteric-coated methylnaltrexone is more efficient in preventing morphine-induced
retardation of oral-to-caecal transit time than the uncoated
preparation [91]. Thus reduced oral bioavailability is associated
with enhanced efficacy, which suggests that oral methylnaltrexone acts locally in the gut to reverse morphine-induced
GI motor stasis. Methylnaltrexone is well tolerated at therapeutic doses (0.3 – 0.45 mg/kg i.v. and ≤ 19.2 mg/kg p.o.)
with no significant adverse reactions, an outcome that is also
true when methylnaltrexone 0.3 mg/kg i.v. is repeatedly
administered every 6 h [41]. The only adverse reaction of note
seen at supra-therapeutic doses (≤ 1.25 mg/kg i.v.) is transient
orthostatic hypotension (Box 1) [88].
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No adverse effects of clinical importance with
methylnaltrexone 0.3 or 1 mg/kg [93]
Alvimopan
Oral administration in healthy volunteers
No significant adverse effects with alvimopan 4 or
12 mg [42,99]
Oral administration in patients receiving chronic opioid
therapy
Bowel-related adverse effects (abdominal cramping,
nausea, vomiting and diarrhoea) with alvimopan 1 mg [100]
Oral administration in patients undergoing surgery that is
likely to result in postoperative ileus
No significant adverse effects and no significant
exacerbation of treatment-emergent adverse effects
postoperatively with alvimopan 1, 6 or 12 mg [101-105]
Nominal enhancement in the proportion of patients
experiencing postoperative nausea and/or vomiting by alvimopan 12 mg during the inpatient period in 1 study [104] as
opposed to a significant reduction in the incidence of
post-operative nausea and vomiting by alvimopan 6 and
12 mg, respectively, in 2 other studies [101,103]
Phase II studies have established that methylnaltrexone is
capable of relieving constipation in methadone-maintained,
opioid-dependent volunteers (Table 1). In a double-blind,
randomised and placebo-controlled trial, it has been found
that intravenous methylnaltrexone shortens the oral-to-caecal
transit time and causes laxation associated with mild
Expert Opin. Investig. Drugs (2007) 16(2)
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Treatment of opioid-induced gut dysfunction
abdominal cramping but does not elicit any signs of opioid
withdrawal [92]. Compared with placebo, oral methylnaltrexone is also capable of provoking laxation in
methadone-maintained patients without precipitating opioid
withdrawal in any subject [93]; however, the latency to the first
bowel movement is significantly longer following oral intake
of the drug than after intravenous administration. The doses
of methylnaltrexone required to induce bowel movements in
subjects on chronic methadone were lower than those
required in subjects who were not opioid dependent (Table 1).
The usefulness of methylnaltrexone to selectively counteract opiate-induced stasis in the GI tract has also been proven
in Phase II and III studies of patients with advanced medical
illness requiring high doses of opiates for pain control [84].
Similarly, patients with postoperative ileus following open
segmental colonic resection have been reported to benefit
from treatment with methylnaltrexone. Thus upper and lower
bowel function recovers ∼ 1 day earlier in patients receiving
intravenous methylnaltrexone than in placebo-treated
patients, whereas no difference in opioid use or mean pain
scores is observed [84]. This report of clinical efficacy is contrasted by an experimental study in rats in which intragastric
methylnaltrexone (100 mg/kg) was found to be inactive in
reversing postoperative inhibition of GI transit in the absence
and presence of postoperative morphine treatment [94].
Following the proof-of-concept with methylnaltrexone, a
µ-opioid receptor-preferring antagonist was developed with a
peripherally restricted site of action and a potency
(MIC = 0.77 nM) ∼ 100-fold higher than that of methylnaltrexone. This compound, alvimopan (ADL 8-2698, formerly known as LY-246736), exhibits both low systemic
absorption (oral bioavailability of 0.03% in dogs and 6% in
humans) and a limited ability to enter the brain due to its
polar structure (Figure 3) [95-97]. Following intravenous administration, the half-life of alvimopan in the systemic circulation
of dogs and rabbits is as short as 10 min. For this reason, alvimopan is intended primarily for oral administration, in which
case it potently blocks µ-opioid receptors in the gut with a
prolonged duration of action. Due to its pharmacokinetic
properties, orally administered alvimopan mainly stays in the
GI tract [95] and the main route of its excretion is via the faecal
route, either in unchanged form or in the form of metabolites
generated by microfloral activity [7,97]. There is no evidence of
drug accumulation following chronic dosing of alvimopan [7].
Studies addressing the acute safety of alvimopan in animals
and humans have shown that the drug is well tolerated; the
only adverse effects of note include nausea, vomiting and
abdominal discomfort [7].
The selectivity of the action of alvimopan for peripheral
opioid receptors was first demonstrated by its ability to elicit
diarrhoea in morphine-dependent mice without reversing
morphine-induced analgesia [98]. In this study, alvimopan was
found to have a prompt onset of action, which lasted for
.
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9.3 Alvimopan
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≥ 8 h [98]. Early Phase I studies established the clinical efficacy
and safety of oral alvimopan [95]. In a double-blind cross-over
study (Table 1), it was found that alvimopan 4 mg was capable
of preventing morphine from delaying GI transit in healthy
subjects as measured by the lactulose hydrogen breath test,
without antagonising central morphine effects such as
analgesia and pupillary constriction [95,99]. Similar results were
obtained in a double-blind, randomised and placebo-controlled trial involving 74 healthy volunteers in which gastric
emptying, and small bowel and colonic transit were assessed
by scintigraphy [42]. Alvimopan 12 mg b.i.d. reversed the
effect of codeine to delay small bowel, proximal and overall
colonic transit but failed to antagonise the effect of codeine to
slow gastric emptying [42].
The clinical testing of alvimopan was subsequently
expanded to explore its usefulness in preventing or treating
OBD and postoperative ileus [7,95-97]. In a randomised and
placebo-controlled study involving 168 patients with OBD
due to chronic opioid therapy for non-malignant pain or opioid addiction (Table 1), alvimopan 0.5 or 1 mg q.d. for
21 days showed significant efficacy in ameliorating constipation without compromising opioid analgesia [100]. The
adverse effects that were associated with alvimopan were primarily bowel related, occurred during the first week of treatment and were of mild-to-moderate severity [100]. Compared
with healthy subjects or patients with postoperative ileus, it
seems that patients receiving chronic opioid treatment are
particularly sensitive to alvimopan [7].
Given that OBD is thought to contribute to postoperative
ileus, several studies have addressed the ability of alvimopan
to shorten postoperative bowel dysfunction (Table 1). An
experimental study in rats has shown that intragastric alvimopan 1 or 3 mg/kg is capable of reversing postoperative
inhibition of GI transit in the absence and presence of postoperative morphine treatment; the effect of alvimopan being
most pronounced when it is administered before surgery [94].
Similar results have been reported in patients with postoperative ileus, although with somewhat varying results,
which may partly have been due to the rather wide range of
doses (1 – 12 mg) tested. In these studies, the initial dose of
alvimopan was usually administered ∼ 2 h before surgery and
the drug subsequently dosed twice daily. Postoperatively,
patient-controlled analgesia with intravenous opioids was
instituted. In a first Phase II trial carried out with 78 patients
who underwent partial colectomy or total abdominal hysterectomy, alvimopan 6 mg (but not 1 mg) shortened the time
to achieve normal bowel function after the operation and the
duration of hospitalisation by a median of 1 day [101]. In addition, the overall incidence of GI side effects including postoperative nausea and vomiting was also reduced by
alvimopan, whereas analgesia was not compromised [101].
Following this promising outcome, several Phase III trials
were initiated, four of which have been published so far
(Table 1). In a placebo-controlled trial involving 469 patients
undergoing bowel resection or radical hysterectomy, it was
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2H2O
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HO
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OH
O
volunteers, in which methylnaltrexone can stimulate GI transit as measured by the lactulose hydrogen breath test [41] and
alvimopan is capable of accelerating colonic transit as measured by scintigraphy [42]. In view of this prokinetic activity, it
has been hypothesised that PRORAs may ameliorate pathological states of GI motor stasis unrelated to opiate use, such
as chronic idiopathic constipation and intestinal
pseudo-obstruction [7,84]. Opioid receptor antagonists are
expected to normalise pathological inhibition of gut function
that arises from an upregulation and/or overactivity of the
opioid system in the GI tract [2]. There is indeed preliminary
evidence that naloxone has beneficial effects in idiopathic
chronic constipation [57], intestinal pseudo-obstruction [57]
and constipation-predominant irritable bowel syndrome [58].
In addition, preliminary data indicate that alvimopan is also
capable of shortening bowel transit time in patients with
chronic constipation [107].
b
Figure 3. Chemical structure of alvimopan.
confirmed that alvimopan 6 and 12 mg accelerated the time
to recovery of GI function by a mean of 15 and 22 h, respectively [102]. The time to writing the hospital discharge order
was shortened on average by 20 h in the group receiving
alvimopan 12 mg [102]. In a similar Phase III study involving
451 patients subjected to partial colectomy or radical hysterectomy, alvimopan 6 mg was found to significantly accelerate
the time to recovery of GI function by a mean of 14 h,
whereas alvimopan 12 mg failed to significantly shorten
recovery of bowel function [103]. In another double-blind,
randomised and placebo-controlled Phase III trial involving
519 women scheduled for simple total abdominal hysterectomy, alvimopan 12 mg was observed to hasten the time to
the first bowel movement by an average of 22 h and to
increase the frequency of bowel movements [104]. Similar
results were found in a study in 615 patients undergoing
laparotomy for bowel resection or hysterectomy, in which
both alvimopan 6 and 12 mg significantly accelerated GI
recovery in terms of toleration of solid food, first bowel
movement and writing of hospital discharge order [105].
In all of these trials, the incidence of adverse events was
similar among the placebo and alvimopan treatment groups
(Box 1) [106]. Postoperatively, the main treatment-emergent
adverse effects were bowel related and included nausea, vomiting and abdominal discomfort. The incidence of postoperative nausea and vomiting was significantly reduced by
alvimopan 6 and 12 mg, respectively, in 2 studies [101,103],
whereas the proportion of patients who experienced nausea
and/or vomiting was nominally enhanced by alvimopan
12 mg in another study [104]. The failure of alvimopan to
antagonise opioid-induced analgesia was confirmed in all of
the studies [100-105].
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tr the mainstay in the treatment of moderOpiates will remain
s
ate-to-severe pain
di in the foreseeable future because the introduction of analgesic drugs with equal efficacy but a more
d safety profile is not yet in sight. Consequently, any
favourable
n
a that improves the tolerability of opioid analgesics
measure
g
represents a progress in the treatment of pain. As outlined in
tinthis review, the GI tract is one of the main sites of the unde-
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10. Opioid
receptor antagonists with a
peripherally restricted site of action as
possible prokinetic drugs
As outlined in Section 5, PRORAs may have potential to alleviate intestinal motor stasis unrelated to opiate use. Thus
naloxone is capable of stimulating peristalsis in the guinea-pig
isolated small intestine [20], which suggests that peripheral
opioid receptor antagonists may have a prokinetic action on
the GI tract [2]. This prediction has been validated in healthy
11. Expert
opinion
sired effects of opiates because the enteric nervous system
expresses all of the key subtypes of opioid receptors that
(when activated) compromise GI function. This may be
physiologically meaningful under conditions where the
endogenous opioid system is activated but represents a nuisance when exogenous opiates are administered for therapeutic purposes. The potential of opiates to cause
constipation and other bowel-related adverse reactions is (in
fact) a serious drawback to the patients’ satisfaction with opioid analgesics. In addition, the use of opioids for postoperative pain control prolongs hospitalisation because of
their potential to enforce and prolong postoperative ileus. As a
result, many opioid-sparing approaches have been explored
but the outcome has generally been unsatisfactory and has at
best resulted in a partial solution of the problem.
The development of opioid receptor antagonists with
restricted access to the CNS has opened up a new approach
to selectively control the adverse actions of opioid analgesics
in the gut. This concept has been validated in an impressive
manner by the clinical evaluation of methylnaltrexone and
alvimopan, which are capable of preventing the undesired
opioid effects on gut function at the same time as preserving
the desired analgesic action of opiates on central pain control. This conclusion has been validated by a recent
meta-analysis of the effect of alvimopan in the treatment of
postoperative ileus [106]. Therefore, it is evident that analgesia
and OBD can be dissociated in a pharmacological manner,
which will theoretically allow for a more aggressive use of
Expert Opin. Investig. Drugs (2007) 16(2)
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Treatment of opioid-induced gut dysfunction
opioid analgesics with better pain relief but fewer side
effects [67]; however, this claim has not yet been substantiated. Although methylnaltrexone and alvimopan display an
excellent safety profile, they have bowel-related adverse
effects of mild-to-moderate severity. It may by speculated
that part of the undesired actions of PRORAs reflect a withdrawal reaction, especially in patients who have a history of
long-term use of opiates.
The concept of pharmacological dissociation of analgesia
and OBD has been proven not only in healthy volunteers but
also in patients with chronic opioid use for pain relief or substitution therapy for addiction. Both methylnaltrexone and
alvimopan have been found to alleviate the symptoms of
OBD without antagonising analgesia or precipitating signs of
opioid withdrawal. Further studies defining optimal dosage
and dosing regimen as well as long-term efficacy and safety are
needed. To date, only 1 study in which alvimopan was given
to patients with OBD due to chronic opioid therapy or opioid addiction for 21 days has been published [100]. In this trial,
alvimopan 1 mg was found to induce a bowel movement in
∼ 50% of the patients, the effect being most prominent
during the first 2 weeks [100].
Several Phase II and III trials have addressed the efficacy of
methylnaltrexone and particularly of alvimopan to hasten the
resolution of postoperative ileus under patient-controlled
opioid analgesia. In assessing these trials, it has to be borne in
mind that there is currently no consensus for defining
postoperative ileus in terms of onset, duration and resolution
of symptoms. Alvimopan and methylnaltrexone were reported
to shorten the time to recovery of GI function (tolerance of
solid food, and passage of flatus or stool) and to writing the
hospital discharge order by variable degrees ≤ 1 day. As no
approved treatment schedule for postoperative ileus exists as
yet, these findings herald a significant advance in the clinical
management of postoperative ileus and are encouraging to
address a number of questions that remain unanswered:
• How does the efficacy of alvimopan and methylnaltrexone,
administered at optimal dosage, in preventing postoperative ileus compare with the efficacy of epidural
anaesthesia/analgesia?
• What are the optimal routes of administration of
alvimopan and methylnaltrexone relative to the conditions
to be treated? As oral alvimopan does not prevent the effect
of codeine to delay gastric emptying [42], it could be argued
that the benefit of alvimopan in postoperative ileus is
limited by the delay of gastric emptying and consequently
by the delay of its delivery to the intestine. Should this drug
be administered by a postpyloric tube to ensure optimal
prokinetic activity?
• Is the therapeutic benefit gained by alvimopan and
methylnaltrexone cost-effective?
• Which group of patients undergoing a particular type of
abdominal surgery benefit most from the ability of
PRORAs to shorten postoperative ileus?
• Does the reported variability in the therapeutic efficacy of
alvimopan reflect different degrees of endogenous opioid
involvement in postoperative ileus?
• As parenteral methylnaltrexone is mostly eliminated by the
renal route, does its dose need to be adjusted in patients
with impaired renal function?
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• Are the effects of alvimopan and methylnaltrexone relevant
for the patient and do they represent a clinically relevant
improvement in terms of shortening the hospital stay for
the patient and reducing ileus-related complications?
• Which dose of alvimopan and methylnaltrexone has the
optimal efficacy/safety profile?
• What is the optimal dosage of alvimopan and
methylnaltrexone in the long-term management of OBD?
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Another important discovery emanating from the clinical
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This attests to the concept that endogenous opioid peptides
play a role in reducing bowel function under physiological
conditions. As there is evidence that the endogenous opioid
system in the gut may be overactive under certain pathological conditions, PRORAs may turn out to be prokinetic
drugs in their own right. Preliminary findings of a therapeutic
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disorders will benefit most from the prokinetic potential of
methylnaltrexone and alvimopan.
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Affiliation
Peter Holzer PhD,
Professor
Research Unit of Translational
Neurogastroenterology, Institute of
Experimental and Clinical Pharmacology,
Medical University of Graz, Universitätsplatz 4,
A-8010 Graz, Austria
Tel: +43 316 380 4500;
Fax: +43 316 380 9645;
E-mail: [email protected]
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