New Drug Class

Novel opioid antagonists for opioid-induced bowel

dysfunction and postoperative ileus
Gerhild Becker, Hubert E Blum

Lancet 2009; 373: 1198–206 Peripherally acting µ-opioid receptor antagonists methylnaltrexone and alvimopan are a new class of drugs designed
Published Online to reverse opioid-induced side-effects on the gastrointestinal system without compromising pain relief. This article
February 13, 2009 gives an overview of the pharmacology, the efficacy, and adverse effects of these drugs. Both compounds seem to be
DOI:10.1016/S0140-
generally well tolerated and effective for the treatment of opioid-related bowel dysfunction and postoperative ileus.
6736(09)60139-2
Methylnaltrexone recently received approval by the US Food and Drug Administration (FDA) and the European
Department of Palliative Care
(G Becker MD) and Department
Medicines Agency for treatment of opioid-related bowel dysfunction in patients with advanced illness. Alvimopan
of Internal Medicine II was recently approved by the FDA for treatment of postoperative ileus, but the use of the drug is restricted to inpatients
(Prof H E Blum MD), University because it has been associated with an increased rate of myocardial infarction. Further research should assess the
Hospital Freiburg, Freiburg,
effectiveness and safety of these drugs in clinical practice.
Germany
Correspondence to:
Dr Gerhild Becker, Department of
Introduction characterised by accumulation of gas and secretions, and
Palliative Care, University The peripherally acting µ-receptor antagonists retention of bowel content, leading to hard stool,
Hospital Freiburg, methylnaltrexone and alvimopan are a new class of drugs incomplete evacuation, bloating, pain, nausea, and
Robert-Koch-Str 3, designed to reverse opioid-induced side-effects on the vomiting.2,5 Opioid-induced bowel dysfuntion can occur
D-79106 Freiburg, Germany
gerhild.becker@
gastrointestinal tract without compromising pain relief. immediately after the first dose and persist for the
uniklinik-freiburg.de Opioids are a mainstay in the treatment of acute and duration of therapy. Unlike many of the other side-effects,
chronic pain—in 2005, opioids were prescribed about patients rarely develop tolerance to the constipating
365 million times worldwide.1 Although opioids are very effects of opioids.6,7 Traditional treatment includes the
effective for pain relief from cancer and non-malignant use of stool softeners, stimulants, and osmotic agents.6–8
diseases, their use is often limited by side-effects. Presently no treatment exists for management of the
The most common side-effect is constipation.2,3 Schug condition beyond laxatives that specifically target the
and colleagues4 showed that in patients with cancer, pharmacological action of opioids.
constipation and vomiting were the most common Postoperative ileus is a block of coordinated bowel
adverse effects associated with opioid therapy. However, motility after surgery.8–10 The pathophysiology is
opioid therapy also affects bowel function by causing multifactorial and incompletely understood.9–11 Major
opioid-induced bowel dysfunction. This largely mechanisms include surgical stress from physical
under-recognised condition is a symptom complex manipulation of the bowel, secretion of inflammatory
mediators, endogenous opioids in the gastrointestinal
tract, and changes to fluid balance, and hormone and
Search strategy and selection criteria electrolyte concentrations.12–14 Opioids given for
We searched Medline, including Medline in Process and other non-indexed citations postoperative pain importantly contribute to the condition
(1950–November, 2008), Embase (1980–November, 2008), Cochrane Database of by inhibition of propulsive gastrointestinal motility.15,16
Systematic Reviews (quarter 4, 2008), Cochrane Central Register of Controlled Trials Furthermore, the evidence for immunomodulatory effects
(quarter 4, 2008), Database of Abstracts of Reviews of Effects (quarter 4, 2008), and of opioids is increasing17–20—eg, the extended phase of
BIOSIS Previews (1969–November, 2008), with the OVID interface, using search terms postoperative ileus is caused by an enteric inflammatory
including “alvimopan”, “methylnaltrexone”, “ADL 8-2698”, “LY246736”, “constipation”, response and recruitment of leucocytes to the muscularis
“intestinal obstruction”, “opioid-induced bowel disease”, and “postoperative ileus”. We also of the bowel wall.16 Leucocytes produce the main inhibitory
searched PubMed (1966–November, 2008), ACP-Journal Club (1991–November, 2008), neurotransmitter of the gastrointestinal tract, nitric oxide,
and CINAHL (1982–November, 2008). We identified articles about peripherally acting through the activity of the inducible isoform of nitric
opioid antagonists and opioid-induced constipation and postoperative ileus, before oxide synthase (iNOS).21 Opioids potentiate iNOS
limiting the search results to clinical trials in human beings. No language restrictions were induction and nitric oxide release from phagocytes;18
placed on the searches. Publications were largely selected from the past 4 years but also therefore, blockage of this opioid-mediated response
included relevant articles from a systematic review (1966–2005, reference 30). We scanned might reverse postoperative ileus.16 The condition can
reference lists of studies from ISI’s Database Web of Science (1945–November, 2008), and cause pain and discomfort, prevent enteral nutrition, and
did internet searches with the terms listed above using the science-specific search engines thereby extend time in hospital.9 Consequently, effective
Scirus and Google Scholar. Further trials were identified from Current Controlled Trials, WHO management is highly desirable.
International Clinical Trials Registry Platform , National Institutes of Health Randomized Treatment for postoperative ileus consists of
Trial Records, and Pharmaceutical Industry Clinical Trials Database. The date of the last intravenous hydration, use of a nasogastric tube,
search was Nov 27, 2008, and we last repeated some of the search on Jan 9, 2009, especially metoclopramide, neostigmine, and the off-label use of
to check for relevant research articles. various drugs—eg, erythromycin or somatostatin.13,22,23
According to a systematic review,22 erythromycin has

1198 www.thelancet.com Vol 373 April 4, 2009


CNS Opioid
Opioids bind to central
µ-opioid receptors to
provide analgesia
Endogenous opioids
Met-enkephalin, leu-enkephalin,
β-endorphin, and dynorphin
(localised in neurons of myenteric
and submucosal plexus, and in
endocrine cells of mucosa)
Exogenous opioids
(eg, morphine and codeine)
Opioid
Gastrointestinal tract
Opioids bind to peripheral
µ-opioid receptors, which
inhibits bowel function
Figure 1: Action of opioids and peripheral μ-opioid receptor antagonists in the CNS and gastrointestinal tract
consistent absence of effect, evidence is insufficient for
cholecystokinin-like drugs (cisapride, dopamine-antag-
onists, propranolol, and vasopressin), and intravenous
lidocaine and neostigmine might show an effect, but
more evidence on clinically relevant outcomes is needed.
Two further drugs are being investigated: atilmotin,24 a
receptor agonist of the endogenous hormone motilin,
which increases upper gastrointestinal tract motility; and
lubiprostone,25,26 a chloride-channel activator that acts
locally in the gut to increase intestinal fluid secretion,
and has been approved by the US Food and Drug
Administration (FDA) for idiopathic chronic obstipation.
Until now, however, no specific treatment has existed to
prevent postoperative ileus or to shorten its course.9,27
Postoperative ileus and opioid-induced bowel dysfuntion
are serious conditions that impose considerable expense
on the health-care system. Retrospective review of the use
of ICD-9 codes to assess postoperative ileus in more than
800 000 US surgical patients, showed that the average
frequency of the condition for all types of surgery
was 4·5%.28 The average length of hospital stay was
9·3 days for patients with postoperative ileus compared
with 5·3 days for those without. For patients with the
condition, mean total hospital costs increased substantially
by US$6300. Application of the occurrence of postoperative
ileus and its related costs to the 42·5 million inpatient
surgeries, which took place in 2002, translates to more
than $11 billion of increased hospital costs.29 Therefore
new drugs such as methylnaltrexone and alvimopan hold
promise for resolving a clinically relevant problem.
Mechanism of action
Receptor-binding studies and molecular cloning
techniques have identified three main classes of opioid
receptors: µ, δ, and κ, with several subtypes in each class.30
These opioid receptors are stimulated by both endogenous
(enkephalins, endorphins, and dynorphins) and exogenous
(morphine and codeine) agonists (figure 1).16,30 Exogenous
www.thelancet.com Vol 373 April 4, 2009
New Drug Class
Opioids continue
No reversal of analgesia
activating µ-opioid
No causation of opioid withdrawal
receptors
µ-opioid
receptor
Blood–brain barrier
Peripheral opioid antagonists
do not cross blood–brain barrier
Peripheral
opioid antagonist
No adverse
gastrointestinal effects
µ-opioid
receptor
Peripheral opioid antagonists dislodge opioid
from µ-opioid receptors in gastrointestinal tract
opioids act predominantly via the µ receptor.7,16 Such
receptors are present in the CNS and peripheral nervous
system (in the CNS they are the primary receptors in pain
management31,32) and enteric µ receptors seem to be the
principal mediator of opioid effects on the gastrointestinal
tract (panel).34,35 Ideally, the adverse gastrointestinal effects
of endogeneous and exogeneous opioids on opiate-related
bowel dysfunction and postoperative ileus would be
specifically inhibited, without reversal of the analgesic
effect of opioids in the CNS. Opioid antagonists with
limited systemic absorption were the first agents to be
used for this purpose—eg, µ-opioid receptor-specific
antagonists naloxone, nalmefene, and naltrexone. These
Panel: Opioid effects in the gastrointestinal tract
Inhibition of enteric nerve activity
• Suppression of enteric nerve excitability
• Presynaptic and postsynaptic inhibition of transmission in
excitatory motor, inhibitory motor, and secretomotor
pathways
• Inhibition of release of substance P, nitric oxide, and
acetylcholine
Inhibition of propulsive motor activity
• Increase of muscle tone
• Inhibition of distension-induced peristalsis
• Induction of non-propulsive motility patterns
• Disturbance of migrating myoelectrical complex
• Inhibition of gastric emptying
• Delay of gastrointestinal transit
Inhibition of secretory activity
• Inhibition of ion and fluid secretion
Immune activity
• Alteration of immune cell function
Adapted from Holzer et al.33
1199
 New Drug Class

obtained exclusive worldwide rights and they formed a

CH3 collaboration with Wyeth Pharmaceuticals, Madison, NJ,
N+ USA, in 2005 to develop and market the compound
H (Relistor). Methylnaltrexone is a quaternary derivative of
naltrexone, which results in a distinct pharmacological
profile (table 1). Addition of a methyl group to the
HO
nitrogen increases polarity and reduces lipid solubility,
Br– and epimer at N+
which prevents the drug crossing the blood–brain
barrier.46–48 Demethylation might allow the tertiary
compound to cross this barrier more readily.
Methylnaltrexone’s metabolism is species-dependent: in
O
O
rats and mice the drug is demethylated over time,
HO H whereas demethylation is negligible in dogs and
Figure 2: Chemical structure of methylnaltrexone bromide primates.49,50 Methylnaltrexone antagonises opioid
For the Martindale website see Structure taken from Martindale. binding at the µ-opioid receptor (median inhibitory
http://www.medicinescomplete.
com/mc/
concentration IC50=70 nmol/L), but has lower affinity to
tertiary antagonists readily crossed the blood–brain barrier the κ receptor (IC50=575 nmol/L), and negligible affinity
and failed to consistently restore gastrointestinal function to the δ receptor.48 Toxicity studies in rats showed a high
without reversing analgesia or inducing opioid median lethal dose of more than 100 mg/kg; in primates
withdrawal.30,36 Subsequently, peripheral opioid antagonists the compound was given in doses of up to 50 mg/kg
that are not systemically absorbed and do not penetrate without mortality.46
the blood–brain barrier were developed, and we will
discuss the novel peripheral antagonists methylnaltrexone Efficacy
and alvimopan. Preclinical and early clinical studies have shown that
methylnaltrexone antagonises opioid-mediated inhibition
Methylnaltrexone of gastrointestinal function in the periphery without
Pharmacology antagonising CNS-mediated effects such as analgesia or
Methylnaltrexone (figure 2) was developed at the pupillary constriction.37,48,51 The peripheral nature of
University of Chicago, Chicago, IL, USA, and out-licensed opioid-receptor antagonism in animal models has been
to UR Labs in 1985. In 2001, Progenics Pharmaceuticals confirmed in healthy volunteers51–53 and members of
methadone programmes to mimic the condition of
patients on opioids (table 2).54,55 Methylnaltrexone is
Methylnaltrexone Alvimopan efficacious for treatment of opioid-induced bowel
Chemistry Derivative of naltrexone; molecular weight Synthetic; molecular weight 460·1 Da; dysfunction when it is given intravenously, sub-
436·3 Da; positively charged zwitterion (dipolar) cutaenously, orally, and orally with an enteric-coated
Receptor Peripheral µ-opioid receptor antagonist; Peripheral µ-opioid receptor antagonist; formulation.51–55,58,59 McNicol’s60 systematic review of four
antagonist 8-fold lower potency at κ-opioid 30-fold lower potency at κ-opioid receptor;37 studies showed that, on average, gastrointestinal transit
receptor;37 120-fold lower potency at δ- 30-fold lower potency at δ-opioid receptor37
opioid receptor37
time in patients given methylnaltrexone was reduced by
Route Intravenous, subcutaneous, and oral Oral
52 min (95% CI –73 to –32 min) compared with
(including enteric-coated) placebo.51,53,54,59 Methylnaltrexone reduced the mean transit
Cmax (ng/mL) 675 (SD 495–855) (0·3 mg/kg*†)38 9·57 (12 mg‡§);37,39 11·3 (SD 6·8–15·8) time to 93–110 min from 140–163 min for palcebo. Phase I
(12 mg†‡);37,40 5·07–15·8 (6, 12, 18, and and II studies have been limited by small sample size
24 mg†‡)37,41 and inherent weaknesses,30 but the methodology of most
tmax (h) 0·10 (SD 0·05–1·15) (0·3 mg/kg*†)38 1·5 (12 mg§)37,39; 2·1 (12 mg†)37,40; 3·0 (12 mg¶, studies is good, and together with preclinical data, these
steady-state values)37,42
studies show proof of concept.
AUC0-∞ 353 (SD 262–444) (0·3 mg/kg*†)38 46·1 (SD 19·1) (12 mg†‡)37,40
(ngh–1mL–1) Subsequently, several randomised double-blind placebo-
t1/2 (h) 2·9 (SD 2·0–3·8) (0·3 mg/kg*†)38 2·4–5·5 (6, 12, 18, and 24 mg†‡)37,41
controlled phase II and III trials have shown efficacy of
Metabolism Small percentage undergoes hepatic Gut flora41,44
methylnaltrexone in patients with advanced illnesses and
metabolism (possibly glucuronidation)43 opioid-induced bowel dysfunction.61–64 One phase III trial
Active None ADL-08-0011, an amide hydrolysis product showed that the drug was at least three times more
metabolite that is generated by gut flora41,44 efficacious than placebo in producing laxation within 4 h
Elimination Mostly eliminated by renal excretion, about Major excretion faecal, minor excretion urine16 of the initial dose, which seemed to be undiminished
40–50% excreted unchanged in urine45 throughout the 3-month open-label extension.56
AUC=area under the curve. *Every 6 h as 12 intravenous doses. †Healthy volunteers. ‡Single oral dose. §Patients older Methylnaltrexone has also been investigated for
than 65 years. ¶Patients with chronic obstipation. prevention of postoperative ileus. A phase II trial showed
treatment accelerated time to first bowel movement and
Table 1: Comparison of pharmacological data for methylnaltrexone and alvimopan
discharge eligibility,57 and phase III trials are continuing.65

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 New Drug Class

Design n Intervention Result

Healthy volunteers
Yuan et al Phase I/II, randomised, 12 Group 1: placebo; group 2: placebo+0·05 mg/kg Oral-caecal transit time (min, mean [SD]): group 1: 104·6 (31·1); group 2:
(1996)51 double-blind, placebo-controlled, morphine; group 3: 0·05 mg/kg morphine+0·45 mg/kg 163·3 (39·8) (p<0·01 vs group 1); group 3: 106·3 (39·8) (not significant vs
crossover methylnaltrexone; all intravenously group 1, p=0·56 vs group 2); methylnaltrexone did not antagonise analgesic
effect of morphine
Murphy Phase I/II, randomised 11 Group 1: placebo; group 2: 0·09 mg/kg morphine; Time for gastric volume to decrease by 50% (min, mean [SD]): group 1: 5·5
et al double-blind, placebo-controlled, group 3: 0·09 mg/kg morphine+0·3 mg/kg (2·1); group 2: 21·0 (9·0) (p<0·03 vs group 1); group 3: 7·4 (3·0) (p<0·04 vs
(1997)52 crossover methylnaltrexone; all intravenously group 2)
Yuan et al Phase II, non-randomised, 14 0·64 mg/kg, 6·4 mg/kg, and 19·2 mg/kg oral Methylnaltrexone was safe and well tolerated up to maximum dose
(1997)53 single-blind, dose-escalating methylnaltrexone
Yuan et al Phase II, randomised, 14 Group 1: oral placebo+intravenous placebo; group 2: Oral-caecal transit (min, mean [SD]): group 1: 114·6 (37·0); group 2: 158·5
(1997)53 double-blind, placebo-controlled oral placebo+0·05 mg/kg intravenous morphine; (50·2) (p<0·001 vs group 1); group 3: 110·4 (45·0) (not significant vs group 1,
group 3: 19·2 mg/kg oral methylnaltrexone p<0·005 vs group 2)
+0·05 mg/kg intravenous morphine
Patients with chronic methadone-induced constipation
Yuan et al Phase II, randomised, 22 Group 1: placebo; group 2: 0·015–0·365 mg/kg Decrease from baseline in oral-caecal transit time (min, mean [SD]): group 1:
(2000)54 double-blind, placebo-controlled methylnaltrexone; all intravenously; both groups tested 1·4 (12); group 2: 77·7 (37·2) (p<0·01 vs group 1); no laxation with group 1 vs
on days 1 and 2 laxation for all of group 2 (p<0·01); no opioid withdrawal symptoms
Yuan et al Phase II, single-blind, dose-ranging 12 Placebo followed next day with: group 1: Time to bowel movement (h, mean [SD]): group 1 (results for 3 of 4 patients):
(2000)55 0·3 mg/kg methylnaltrexone; group 2: 1·0 mg/kg 18·0 (8·7); group 2 (4 of 4 patients): 12·3 (8·7); group 3 (4 of 4 patients):
methylnaltrexone; group 3: 3·0 mg/kg 5·2 (4·5); dose-response effect with drug, p=0·04; no adverse effects; no
methylnaltrexone; all orally opioid withdrawal symptoms
Patients with advanced illness and opioid-induced bowel dysfunction
Thomas Phase III, randomised, 133 Group 1: placebo; group 2: 0·15 mg/kg Proportion of patients that laxated within 4 h of first dose: group 1: 48·4%;
et al double-blind, placebo-controlled methylnaltrexone; all subcutaneously every other day, group 2: 15·5%; 33% difference (95% CI 7%–49%; p<0·0001); no opioid
(2008)56 for 2 weeks withdrawal symptoms
Patients with postoperative ileus
Viscusi Phase II, randomised, 65 Group 1: placebo; group 2: 0·3 mg/kg Time to first bowel movement (h, mean [SD]): group 1: 120 (10); group 2: 97
et al double-blind, placebo-controlled, methylnaltrexone; every 6 h by intravenous infusion for (6) (p=0·01 vs group 1); time to discharge eligibility (h, mean [SD]): group 1:
(2005)57 90 min after segmental colectomy 7 days or up to 24 h after gastrointestinal recovery 149 (17); group 2: 119 (7) (p=0·03 vs group 1)

Table 2: Clinical studies with methylnaltrexone

Additionally the drug has several interesting features
when given intravenously,66 which need further
eludication: reduction of opioid-induced urinary
retention,67 reversal of opioid-induced cough reflex
suppression,68 and inhibition of both opioid-induced
angiogenesis and opioid-receptor-independent vascular
endothelial growth factor receptor transactivation.69
Adverse effects
Pharmacokinetic study of the safety profile of
methylnaltrexone identified the dose-limiting
adverse effect—orthostatic hypotension—at plasma
concentrations in excess of 1400 ng/mL; the effect was
transient and self-limiting. Consequently, an upper
dose limit of 0·3 mg/kg was chosen for further clinical
assessment,53 a dose that is well tolerated in healthy
volunteers, in members of methadone maintenance
programmes, and in different clinical populations. The
most common adverse effects are abdominal cramps
and flatulence.38,54,70 In a phase III placebo-controlled
trial in 133 patients with opioid-induced bowel disorder
and advanced illnesses, abdominal pain was reported
by 17% of patients (vs 13% of placebo group), flatulence
by 13% of patients (vs 7% of placebo group), and nausea
by 11% of patients (vs 7% of placebo group).56 Rare
adverse events might only be seen with long-term use
of methylnaltrexone in larger populations than those
previously studied.
Alvimopan
Pharmacology
After peripherally-acting methylnaltrexone was shown to
be effective, the synthetic molecule alvimopan was
developed (figure 3). The drug (Entereg) was initially
reported in 1994 by Eli Lilly71 and is presently being
co-developed by Adolor Corporation, Exton, PA, USA,
and GlaxoSmithKline. Alvimopan is a quarternary
µ-opioid receptor antagonist with a different pharmaco-
logical profile from methylnaltrexone (table 1).72 The
high-molecular-weight zwitterionic form and polarity
restrict gastrointestinal absorption and prevent the drug
crossing the blood–brain barrier.7 Compared with
methylnaltrexone, in-vitro data show that alvimopan has
a higher binding affinity for human µ-opioid receptors
and is more potent.73,74 Unlike methylnaltrexone, alvimo-
pan has an active metabolite—ADL-08-0011—which is
produced by amide hydrolysis in human gut flora,41,44 and
seems to be absorbed systemically. In vitro, the metabolite
is equipotent to alvimopan, but its contribution to clinical
effectiveness is unknown.44
The pharmacokinetic profile of the drug is characterised
by an oral bioavailability of only 6%, which results in

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 New Drug Class
N patients in the US and Canadian studies of alvimopan in
OH
O N
H alvimopan via patient-controlled analgesia in the
H3C
HO
O
CH3
Figure 3: Chemical structure of anhydrous alvimopan
Structure taken from Martindale.
predominant activity on the gut itself.16 Alvimopan does
not seem to be metabolised by cytochrome P450,
glucuronidation, or sulphation, and the major route of
excretion is faecal.16 Pharmacokinetic study of patients
with renal impairment who were given a single oral dose
of 12 mg showed that there was no relation between renal
function and plasma alvimopan.40
Efficacy
Preclinical studies showed that alvimopan is a potent
antagonist of opioid-mediated inhibition of gastrointestinal
function, without antagonising CNS-mediated effects such
as analgesia or pupillary constriction.16,37 Effects in animal
models have been confirmed in healthy volunteers,75,76 and
in patients given opioid therapy for chronic pain or
methadone addiction (table 3).70,72 The efficacy of alvimopan
in opioid-induced bowel dysfunction has been shown in
phase II/III clinical studies, in which median time to first
bowel movement decreased significantly78 and mean
weekly bowel movement increased significantly.79
McNicol’s60 systematic review assessed the efficacy of
alvimopan for the prevention of postoperative ileus from
five placebo-controlled trials, which enrolled a total of
2225 patients at risk.80–84 The combined outcomes showed
that time to first bowel movement or flatus, or total time to
tolerate solid food and pass flatus or stool, was quicker
with alvimopan than with placebo. Increase of the daily
dose from 6 mg to 12 mg did not offer an advantage, and
no difference in pain scores (visual analogue scale) was
reported between alvimopan and placebo. 39 (4%) of
956 patients given alvimopan compared with 63 (10%) of
648 patients given placebo reported having ileus, translating
to an absolute risk reduction of 4% (95% CI –7 to –1).
A large multicentre trial in Europe and New Zealand15
showed a reduction of the mean time to tolerate solid
food and the time to either first flatus or bowel movement
in patients with postoperative ileus who were treated with
alvimopan. By contrast with US and Canadian studies,81–83
however, this effect was not statistically significant.15 An
1202
exploratory post-hoc analysis15 showed that in the
subgroup receiving opioids for postoperative pain via
intravenous patient-controlled analgesia, statistically
gastrointestinal recovery was significantly faster in the
treated group than in the placebo group. In this European
and New Zealand study,15 69% of patients were given
non-opioid analgesics in the first 48 h after surgery.
Büchler and colleagues15 report that the proportion of
postoperative ileus,81–83 in which most patients used
patient-controlled analgesia, was substantially lower at
only 4%. Therefore, the response of patients treated with
European and New Zealand study15 is consistent with the
findings in the US and Canadian trials,81–83 with respect to
recovery of gastrointestinal function.
Adverse effects
McNicol60 also analysed the safety data from nine
placebo-controlled trials of alvimopan in healthy
volunteers,75–77 in patients given chronic opioid therapy,78
or in patients after surgery who were at risk of
postoperative ileus.80–84 Surprisingly, the proportion of
gastrointestinal-related adverse events was lower in
patients treated with alvimopan than with placebo, which
suggests that gastrointestinal outcomes are measures of
efficacy rather than safety.60 As might be expected, most
studies suggested a reduction of the prevalence and
severity of constipation, postoperative ileus, and
vomiting—eg, one study showed a substantial reduction
of nausea in 26 patients post-surgery who were given
6 mg of alvimopan daily.80 However, statistically significant
reduction of nausea with alvimopan was not seen by
meta-analysis with a fixed-effect model as an overall class
effect.60 Similar to data suggesting that intravenous
methylnaltrexone reduces opioid-induced urinary
retention,67 meta-analysis60 of two studies of alvimopan in
patients after surgery81,83 showed reduced reports of
oliguria with an absolute risk reduction of 4% (95% CI
–7 to –1; ie, not formally statistically significant). A study
in patients on chronic opioid therapy with opioid-induced
bowel dysfunction78 showed an increased prevalence of
diarrhoea in patients treated with alvimopan, with an
absolute risk increase of 11% (95% CI 2 to 19), but there
was no difference in the other populations studied or in
those given methylnaltrexone. One study79 suggested that
for patients with non-cancer pain and opioid-induced
bowel dysfunction, 0·5 mg of alvimopan twice daily had
the best benefit-to-risk profile. Generally, more safety
data are available for alvimopan than for methyl-
naltrexone,60 but both seem to be well tolerated.
These promising results made it probable that the FDA
would approve the 12 mg dose of alvimopan to treat
postoperative ileus. However, the letter of approval,
issued in November, 2006, called for additional safety
data and a risk-management plan12 because of the results
from a 12-month study.86 The study86 was designed to
www.thelancet.com Vol 373 April 4, 2009
 New Drug Class

assess the long-term safety and tolerability of alvimopan
in patients taking opioids for chronic non-cancer pain
and who had opioid-induced bowel dysfunction. Of
805 patients randomised 2:1—538 given alvimopan
(0·5 mg twice daily) and 267 given placebo—the
proportion of serious adverse events was similar in both
groups (13% vs 11%), but there was a numerical imbalance
in the proportion of neoplasms (2·8% vs 0·7%) and an
increased proportion of myocardial infarctions (n=7
[1·3%] vs n=0). However, the serious cardiovascular
adverse events arose in patients with established or high
risk of cardiovascular disease and, since most events took

Design n Intervention Result

Healthy volunteers
Liu et al Phase I/II, randomised, 14 Group 1: oral placebo+intravenous placebo; group 2: Gastrointestinal transit time (min, mean [SD]): group 1: 69 (33); group 2: 103 (37); group 3:
(2001)75 double-blind, oral placebo+0·05 mg/kg intravenous morphine; 76 (30) (p=0·004 vs group 2)
placebo-controlled, group 3: 4 mg oral alvimopan+0·05 mg/kg
crossover intravenous morphine; washout period of 5 days
Liu et al Phase II, randomised, 45 Group 1: 4 mg oral alvimopan+0·15 mg/kg Pupil size, area under plasma concentration time curve; (mean [SD]); group 1: 453 (168);
(2001)75 double-blind, intravenous morphine; group 2: oral group 2: 423 (175); group 3: 44 (84) (p<0·001 vs group 2; p<0·001 vs group 1); categorical
placebo-controlled study placebo+0·15 mg/kg intravenous morphine; pain and pain relief scores showed significant analgesia with morphine that was unaffected
(healthy volunteers after group 3: oral placebo+intravenous placebo by alvimopan
dental surgery)
Barr et al Phase II, randomised, 11 Group 1: 30 mg morphine+placebo; group 2: 30 mg Colonic motility (marker score with radio-opaque markers, mean [SD]); group 1: 248 (88);
(2000)77 double-blind, morphine+3 mg alvimopan; all orally for 4 days, group 2: 140 (88) (p<0·01 vs group 1)
placebo-controlled, morphine twice a day, placebo or alvimopan three
crossover times a day, washout period 10 days
Patients with chronic methadone-induced constipation or opioid-induced bowel dysfunction
Schmidt Phase II, randomised, 75 Group 1: placebo; group 2: 0·5 mg alvimopan; Proportion of patients with bowel movement within 12 h: group 1: 30%; group 2: 65%;
(2001)72 double-blind, group 3: 1·5 mg alvimopan; group 4: 3·0 mg group 3: 77%; group 4: 100%; (p<0·001 for overall treatment with alvimopan)
placebo-controlled alvimopan; all orally and single dose
Paulson Phase II/III, randomised, 168 Group 1: placebo; group 2: 0·5 mg alvimopan; Time to first bowel movement (h, median): group 1: 21; group 2: 7; group 3: 3 (hazard ratio
et al double-blind, group 3: 1·0 mg alvimopan; all orally, once a day vs group 1 2·29 [95% CI 1·55–3·39; p<0·001])
(2005)78 placebo-controlled
Webster Phase II/III, randomised, 522 Group 1: placebo; group 2: 0·5 mg alvimopan twice Change in spontaneous bowel movement frequency compared with group 1 (weekly, mean
et al double-blind, a day; group 3: 1·0 mg alvimopan once a day; [95% CI]): group 2: 1·71 (0·83–2·58); group 3: 1·64 (0·88–2·40); group 4: 2·52 (1·40–3·65);
(2008)79 double-dummy, group 4: 1·0 mg alvimopan twice a day; all orally (p<0·001 for all comparisons)
placebo-controlled
Patients with postoperative ileus
Büchler Phase III, randomised, 911 Group 1: oral placebo; group 2: 6 mg alvimopan; Time to recovery of gastrointestinal functions (composite endpoint) (h, mean [SE]): group 1:
et al double-blind, group 3: 12 mg alvimopan; all orally twice a day; 92·6 (3·06); group 2: 84·2 (2·37); group 3: 87·8 (2·68); difference in time to recovery of
(2008)15 placebo-controlled opioids for postoperative pain were administered as gastrointestinal function compared with group 1 (h, mean [95% CI]): group 2: –8·5 (–16·0 to
patient-controlled analgesia or bolus injection –0·9) (p=0·042) (non-significant because threshold was p<0·025 for application of
Hochberg’s method to correct for multiple comparisons); group 3: –4·8 (–12·8 to 3·2)
(p=0·20); an exploratory post-hoc analysis showed that alvimopan was more effective in the
patient-controlled analgesia group than in the bolus injection group
Taguchi Phase III, randomised, 79 Group 1: placebo; group 2: 1 mg alvimopan twice a Hazard ratio of time to first bowel movement compared with group 1:(95% CI); group 2: 1·2
et al double-blind, day; group 3: 6 mg alvimopan twice a day; all orally (0·5–2·6); group 3: 2·9 (1·3–6·6); (p=0·01 for both comparisons)
(2001)80 placebo-controlled
Wolff Phase III, randomised, 510 Group 1: placebo; group 2: 6 mg alvimopan; Hazard ratio of time to recovery of gastrointestinal functions (composite endpoint)
et al double-blind, group 3: 12 mg alvimopan; all orally twice a day compared with group 1 (95% CI): group 2: 1·28 (1·00–1·64) (p<0·05); group 3: 1·54
(2004)81 placebo-controlled (1·21–1·96) (p<0·001)
Delaney Phase III, randomised, 451 Group 1: placebo; group 2: 6 mg alvimopan; Hazard ratio of time to recovery of gastrointestinal functions (composite endpoint)
et al double-blind, group 3: 12 mg alvimopan; all orally twice a day compared with group 1 (95% CI): group 2: 1·45 (1·13–1·85) (p=0·003); group 3: 1·28
(2004)82 placebo-controlled (0·99–1·64) (p=0·059)
Viscusi Phase III, randomised, 615 Group 1: placebo; group 2: 6 mg alvimopan; Hazard ratio of time to recovery of gastrointestinal functions (composite endpoint)
et al double-blind, group 3: 12 mg alvimopan; all orally twice a day compared with group 1 (95% CI): group 2: 1·24 (1·01–1·53) (p=0·037); group 3: 1·26
(2001)83 placebo-controlled (1·03–1·54) (p=0·028); results adjusted for covariates—eg, sex or surgical duration
Herzog Phase III, randomised, 519 Group 1: placebo; group 2: 12 mg alvimopan; all Time to first bowel movement and toleration of solid food (composite endpoint)
et al double-blind, orally twice a day (h, mean): group 1: 92·0; group 2: 71·8; difference –20·2 h (95%CI –26·5 to –13·9);
(2006)84 placebo-controlled alvimopan accelerated time to first bowel movement (hazard ratio 2·33, p<0·001); similar
proportion of adverse events: 6·5% in group 1, 5·6% in group 2
Kirk et al Phase III, randomised, 654 Group 1: placebo; group 2: 12 mg alvimopan orally Hazard ratio of time to first bowel movement and toleration of solid food (composite
(2008)85 double-blind, twice a day; both groups followed a standardised endpoint) compared with group 1 (95% CI): 1·5 (1·29–1·82) (p<0·001)
placebo-controlled accelerated postoperative care pathway (early
ambulation, oral feeding, and nasogastric tube
removal) to help with gastrointestinal tract recovery

Table 3: Clinical studies with alvimopan

www.thelancet.com Vol 373 April 4, 2009 1203

 New Drug Class
place within the first 12 weeks of treatment, these events
did not seem to be linked to the duration of dosing.86
Adolor Corporation submitted a revised risk-management
programme for alvimopan in February, 2008, and
alvimopan was approved in May, 2008, for the management
of postoperative ileus with a Risk Evaluation and Mitigation
Strategy (REMS).87 REMS is designed to ensure that the
benefits of the drug outweigh the risks and includes:
restriction to inpatient use only, hospitals should be
specially certified, educational material should be
distributed to health-care professionals, and the
effectiveness of the REMS should be regularly assessed.
Conclusions
Methylnaltrexone and alvimopan are better than placebo
for reversal of opioid-mediated increase of gastrointensinal
transit time and constipation.60 At therapeutic intravenous
doses of 0·3–0·45 mg/kg and oral doses up to 19 mg/kg,
methylnaltrexone is well tolerated and able to relieve
constipation in methadone-dependent individuals and
patients with advanced illnesses who need high doses of
opioids for pain control.48,88 Consequently, the FDA and
the European Medicines Agency have approved
subcutaneous methylnaltrexone for treatment of
opioid-induced constipation in adults with advanced
illnesses. Methylnaltrexone should be used in patients
with opioid-induced bowel dysfunction who do not have
a response to a reasonable laxative regimen, in
combination with the laxative regimen. The recommended
dose is 8 mg for patients weighing 38–61 kg and 12 mg
for patients weighing 62–114 kg, every 2 days. Outside
these weight ranges, the dose should be 0·15 mg/kg.74
Defaecation can be expected within 4 h after the first dose
in about 50% of patients.56
Alvimopan is effective in patients with postoperative
ileus at doses of 6 mg or 12 mg daily and the drug is
approved by the FDA for accelerated restoration of
normal bowel function in patients aged 18 years and over
who have undergone partial resection surgery on the
large or small bowel. The recommended dose is one
12 mg capsule just before surgery and another 12 mg
dose twice daily for up to 7 days, but not exceeding
15 doses.
Despite the high probability of effectiveness, the use of
both drugs will be limited by expense. From personal
communication with the manufacturers, we are informed
that a single dose of 12 mg methylnaltrexone costs about
€50–55 in Europe and the market price for one single
dose of 12 mg alvimopan in the USA is US$52·50
(US$1=€0·75). Cost-effectiveness studies investigating
the incremental costs per quality-adjusted life-year are
needed, as suggested by the UK National Institute for
Health and Clinical Excellence.89
Presently, direct comparison between methylnaltrexone
and alvimopan is not possible, because such large-
scale clinical trials have not yet been done. Alvimopan
seems to have higher pharmacological potency than
1204
methylnaltrexone,73,74 but methylnaltrexone can be given
via different routes, which might be beneficial for early
postoperative or terminally ill patients, whereas
alvimopan is available only orally. Methylnaltrexone also
seems to have positive intrinsic µ-opioid receptor
functional activity, consistent with partial antagonism,
unlike alvimopan and ADL-08-0011, which have negative
intrinsic activities.90 Conceivably, an inverse agonist
would produce a larger clinical effect than a partial
agonist because of a more complete reversal of action of
highly efficacious agonists such as morphine. But the
validity of this hypothesis and the clinical significance of
these differences remain to be determined. Other
potentially relevant clinical differences between
alvimopan and methylnaltrexone should be investigated
in future clinical trials.
Most studies of methylnaltrexone and alvimopan
measure efficacy. The treated and control groups are
homogeneous, confounding variables are controlled, and
bias is reduced. Therefore, internal validity of the studies
is comparatively high, although some studies used a
pseudo-intention-to-treat principle rather than a real
intention-to-treat analysis. But the external validity of the
studies to the general population of patients—eg, those
with cancer—is low. To assess effectiveness, there is a
need for studies assessing clinical practice and reflecting
real-life circumstances. Larger trials are needed to examine
the effects of opioid antagonists on pain control, to
determine proper dosing, and to compare opioid
antagonist efficacy with standard adjuvant therapy.
Furthermore, early postoperative patients or those with
advanced illnesses often receive several drugs and the
possible pharmacological interactions or the effects of
enzyme induction by comedications are unknown and
need future investigation in large groups of patients and
clinical trials.
Conflict of interest statement
We declare that we have no conflict of interest.
Acknowledgments
We thank Sabine Buroh, librarian at the University Hospital Freiburg, for
her assistance with the electronic literature search, and Erika Graf,
statistician from the clinical trials centre in the University Hospital
Freiburg, for her assistance with calculating the 95% CI in some studies.
References
1 Panchal SJ, Müller-Schwefe P, Wurzelmann JI. Opioid-induced bowel
dysfunction: prevalence, pathophysiology and burden. Int J Clin Pract
2007; 61: 1181–87.
2 Pappagallo M. Incidence, prevalence, and management of opioid
bowel dysfunction. Am J Surg 2001; 182 (suppl 5a): 11S–18S.
3 Sykes NP. The relationship between opioid use and laxative use in
terminally ill cancer patients. Palliat Med 1998; 12: 375–82.
4 Schug SA, Zech D, Grond S, Jung H, Meuser T, Stobbe B.
A long-term survey of morphine in cancer patients.
J Pain Symptom Manage 1992; 7: 259–66.
5 Kurz A, Sesser I. Opiate-induced bowel dysfunction: pathophysiology
and potential new therapies. Drugs 2003; 63: 649–71.
6 McNicol E, Horowicz-Mehler N, Fisk RA, et al. Management of opioid
side-effects in cancer-related and chronic noncancer pain:
a systematic review. J Pain 2003; 4: 231–56.
7 Thomas J. Opioid-induced bowel dysfunction.
J Pain Symptom Manage 2008; 35: 103–13.
www.thelancet.com Vol 373 April 4, 2009

8 Fakata KL, Cole BE. Peripheral opioid antagonists: a therapeutic
advance for optimizing opioid gastrointestina tolerability.
J Fam Pract 2007; 56 (suppl 6): S3–12.
9 Stewart D, Waxman K. Management of posteroperative ileus.
Am J Ther 2007; 14: 561–66.
10 Kehlet H, Holte K. Review of postoperative ileus. Am J Surg 2001;
182 (suppl 5A): 3S–10S.
11 Leslie JB. Alvimopan: a peripherally acting mu-opioid receptor
antagonist. Drugs Today (Barc) 2007; 43: 611–25.
12 Kraft MD. Emerging pharmacologic options for treating
postoperative ileus. Am J Health Syst Pharm 2007; 64: S13–20.
13 Bauer AJ, Boeckxstaens GE. Mechanisms of postoperative ileus.
Neurogastroenterol Motil 2004; 16 (suppl 2): 54–60.
14 Delaney CP, Wolff BG, Viscusi ER, et al. Alvimopan for
postoperative ileus following bowel resection. Ann Surg 2007;
245: 355–63.
15 Büchler MW, Sieler CM, Monson JRT, et al. Clinical trial: alvimopan
for the management of post-operative ileus after abdominal surgery:
results of an international randomized, double-blind, multicentre,
placebo-controlled clinical study. Aliment Pharmacol Ther 2008;
28: 312–25.
16 Camilleri M. Alvimopan, a selective peripherally acting µ-opioid
antagonist. Neurogastroenterol Motil 2005; 17: 157–65.
17 Gomez-Flores R, Rice KC, Zhang X, Weber RJ. Increased tumor
necrosis factor-α and nitric oxide production by rat macrophages
following in vitro stimulation and intravenous administration of the
δ-opioid agonist SNC 80. Life Sci 2001; 68: 2675–84.
18 Kowalski J. Augmenting effect of opioids on nitrite production by
stimulated murine macrophages. Neuropeptides 1998; 32: 287–91.
19 Gomez-Flores R, Weber RJ. Immunomodulation of macrophage
functions by opioids. Adv Exp Med Biol 1998; 437: 13–19.
20 Narayan P, Singh VK, Agarwal SS, et al. Immunmodulation by
opioid peptidomimetic compound. Neuroimmunomodulation 2001;
9: 134–40.
21 Kalff JC, Schraut WH, Billiar TR, Simmons RL, Bauer AJ. Role of
inducible nitric oxide synthase in postoperative intestinal smooth
muscle dysfunction in rodents. Gastroenterology 2000; 118: 316–27.
22 Traut U, Brügger L, Pauli-Magnus C, et al. Systemic prokinetic
pharmacologic treatment for postoperative adynamic ileus
following abdominal surgery in adults. Cochrane Database Syst Rev
2008; 1: CD004930.
23 Behm B, Stollmann N. Postoperative ileus: etiologies and
interventions. Clin Gastroenterol Hepatol 2003; 1: 71–80.
24 Peeters TL. New motilin antagonists: a long and winding road.
Neurogastroenterol Motil 2006; 18: 1–5.
25 Tuteja AK, Rao SS. Lubiprostone for constipation and irritable
bowel syndrome with constipation. Expert Rev Gastroenterol Hepatol
2008; 2: 727–33.
26 Saad R, Chey WD. Lubiprostone for chronic idiopathic constipation
and irritable bowel syndrome with constipation.
Expert Rev Gastroenterol Hepatol 2008; 2: 497–508.
27 Maron DJ, Fry RD. New therapies in the treatment of postoperative
ileus after gastrointestinal surgery. Am J Ther 2008; 15: 59–65.
28 Saunders WB, Bowers B, Moss B, Bell TJ, Wang PF. Recorded rate
and economic burden associated with postoperative ileus. 39th
American Society of Health-System Pharmacists Midyear Clinical
Meeting and Exhibits; Orlando, FL; Dec 5–9, 2004. Abstr P440E.
29 Wittbrodt E. The impact of postoperative ileus and emerging
therapies. Pharm Treat 2006; 31: 39–59.
30 Becker G, Galandi D, Blum HE. Peripherally acting opioid
antagonists in the treatment of opiate-related constipation: a
systematic review. J Pain Symptom Manage 2007; 3: 547–65.
31 Friedman JD, Bello Buono FA. Opioid antagonists in the treatment
of opiate-induced constipation and pruritus. Ann Pharmacother
2001; 35: 85–91.
32 Knowles CH, Martin JE. Slow transit constipation: a model of
human gut dysmotility. Review of possible aetiologies.
Neurogastroenterol Motil 2000; 12: 181–96.
33 Holzer P. Treatment of opioid-induced gut dysfunction.
Expert Opin Investig Drugs 2007; 16: 181–94.
34 Sternini C, Patierno S, Selmer IS, Kirchgessner A. The opioid system
in the gastrointestinal tract. Neurogastroenterol Motil 2004;
16 (suppl 2): 3–16.
www.thelancet.com Vol 373 April 4, 2009
New Drug Class
35 De Schepper HU, Cremonini F, Park MI, Camilleri M. Opioids and
the gut: pharmacology and current clinical experience.
Neurogastroenterol Motil 2004; 16: 383–94.
36 Neyens R, Jackson KC. Novel opioid antagonists for opioid-induced
bowel dysfunction and postoperative ileus.
J Pain Palliat Care Pharmacother 2007; 21: 27–33.
37 DeHaven-Hudkins DL, DeHaven RN, Little PJ, Techner LM. The
involvement of the µ-opioid receptor in gastrointestinal
pathophysiology: therapeutic opportunities for antagonism at this
receptor. Pharmacol Ther 2008; 17: 162–87.
38 Yuan CS, Doshan H, Charney MR, et al. Tolerability, gut effects, and
pharmacokinetics of methylnaltrexone following repeated
intravenous administration in humans. J Clin Pharmacol 2005;
45: 538–46.
39 Foss J, Marbury TC, Melikian A, Schmith V, Du W, Wallin B.
Pharmacokinetics and safety of alvimopan, a novel, oral peripherally
acting mu-opioid receptor (PAM-OR) antagonist in the elderly.
Pharmacotherapy 2005; 25: 1505 (abstr).
40 Foss J, Marbury TC, Melikian A, Schmith V, Du W, Wallin B.
Pharmacokinetics and safety of alvimopan, a novel, oral peripherally
acting mu-opioid receptor (PAM-OR) antagonist in patients with
renal impairment. Pharmacotherapy 2005; 25: 1504 (abstr).
41 Foss J, Schmith V, Wallin B, Du W, Melikian A. Alvimopan
(Entereg), a novel opioid antagonist, achieves active systemic
concentrations. Clin Pharmacol Ther 2005; 77: P74 (abstr).
42 Schmith V, Garnett W, Barr WH, et al. Alvimopan pharmacokinetics
(PK) and pharmacodynamics (PD) in patients with chronic
constipation. Clin Pharmacol Ther 2005; 77: P49 (abstr).
43 Yuan CS, Israel RJ. Methylnaltrexone, a novel peripheral opioid
receptor antagonist for the treatment of opioid side-effects.
Expert Opin Investig Drugs 2006; 15: 541–52.
44 Foss JF, Fisher DM, Schmith VD. Pharmacokinetics of alvimopan
and its metabolite in healthy volunteers and patients in
postoperative ileus trials. Clin Pharmacol Ther 2008; 83: 770–76.
45 De Ponti F. Methylnaltrexone. Curr Opin Investig Drugs 2002;
3: 614–20.
46 Brown DR, Goldberg LI. The use of quaternary narcotic
antagonists in opiate research. Neuropharmacology 1985; 24: 181–91.
47 Russell J, Bass P, Goldberg LI, Schuster CR, Merz H. Antagonism
of gut, but not central effects of morphine with quaternary narcotic
antagonists. Eur J Pharmacol 1982; 78: 255–61.
48 Yuan CS, Israel RJ. Methylnaltrexone, a novel peripheral opioid
receptor antagonist for the treatment of opioid side-effects.
Expert Opin Investig Drugs 2006; 15: 541–52.
49 Kotake AN, Kuwahara SK, Burton E, McCoy CE, Goldberg LI.
Variations in demethylation of N-methylnaltrexone in mice, rats,
dogs, and humans. Xenobiotica 1989; 19: 1247–54.
50 Holzer P. Opioids and opioid receptors in the enteric nervous
system: from a problem in opioid analgesia to a possible new
prokinetic therapy in humans. Neurosci Lett 2004; 361: 192–95.
51 Yuan CS, Foss JF, O’Connor M, Toledano A, Roizen MF, Moss J.
Methylnaltrexone prevents morphine-induced delay in oral-cecal
transit time without affecting analgesia: a double-blind
randomized placebo-controlled trial. Clin Pharmacol Ther 1996;
59: 469–75.
52 Murphy DB, Sutton JA, Prescott LF, Murphy MB. Opiate-induced
delay in gastric emptying: a peripheral mechanism in humans.
Anesthesiology 1997; 87: 765–70.
53 Yuan CS, Foss JF, Osinski J, Toledano A, Roizen MF, Moss J. The
safety and efficacy of oral methylnaltrexone in preventing
morphine-induced delay in oral-cecal transit time.
Clin Pharmacol Ther 1997; 61: 467–75.
54 Yuan CS, Foss JF, O’Connor M, et al. Methylnaltrexone for reversal
of constipation due to chronic methadone use. JAMA 2000;
283: 367–72.
55 Yuan CS, Foss JF. Oral methylnaltrexone for opiate-induced
constipation. JAMA 2000; 284: 1383–84.
56 Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for
opioid-induced constipation in advanced illness. N Engl J Med
2008; 358: 2332–43.
57 Viscusi E, Rathmell J, Fichera A, Gan TL, Israel RJ. A double-blind,
randomized, placebo-controlled trial of methylnaltrexone (MNTX)
for post-operative bowel dysfunction in segmental colectomy.
Proc Am Soc Anesth 2005; 103: A893 (abstr).
1205
 New Drug Class
58 Yuan CS, Foss JF, O’Connor M, et al. Effects of enteric-coated
methylnaltrexone in preventing opioid-induced delay in oral-cecal
transit time. Clin Pharmacol Ther 2000; 67: 398–404.
59 Yuan CS, Wei G, Foss JF, O’Connor M, Karrison T, Osinski J.
Effects of subcutaneous methylnaltrexone on morphine-induced
peripherally mediated side-effects: a double-blind randomized
placebo-controlled trial. J Pharmacol Exp Ther 2002; 300: 118–23.
60 McNicol ED, Boyce D, Schumann R, Carr DB. Mu-opioid
antagonists for opioid-induced bowel dysfunction.
Cochrane Database Syst Rev 2008; 2: CD006332.
61 Thomas J, Portenoy R, Moehl M, et al. A phase II randomized
dose-finding trial of methylnaltrexone for the relief of
opiate-induced constipation in hospice patients.
Proc Am Soc Clin Oncol 2003; 22: 729 (abstr 2933).
62 Portenoy R, Thomas J, Moehl Boatwright ML, et al. Subcutaneous
methylnaltrexone for the treatment of opioid-induced constipation
in patients with advanced illness: a double-blind, randomized,
parallel group, dose-ranging study. J Pain Symptom Manage 2008;
35: 458–68.
63 Thomas J, Lipman A, Slatkin N, et al. A phase III double-blind
placebo-controlled trial of methylnaltrexone (MNTX) for
opioid-induced constipation (OIC) in advanced medical illness (AMI).
ASCO Annual Meeting; Orlando, FL; May 13–17, 2005. Abstr 8003.
http://opd.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/
Abstracts?&vmview=abst_detail_view&confID=34&abstractID=32585
(accessed Jan 10, 2009).
64 Karver S, Israel RJ. Methylnaltrexone improves opioid-induced
constipation and reduces laxative use in patients with advanced
illness. Gastroenterology 2007; 132 (suppl 2): A478 (abstr).
65 Wyeth Pharmaceuticals. Wyeth and Progenics begin phase II
and III trials of methylnaltrexone for OIC and POI. Madison, NJ:
Wyeth Pharmaceuticals.
66 Reichle FM, Conzen PF. Methylnaltrexone, a new peripheral
µ-receptor antagonist for the prevention and treatment of
opioid-induced extracerebral side-effects. Curr Opin Investig Drugs
2008; 9: 90–100.
67 Rosow CE, Gomery P, Chen TY, Stefanovich P, Stambler N,
Israel R. Reversal of opioid-induced bladder dysfunction by
intravenous naloxone and methylnaltrexone. Clin Pharmacol Ther
2007; 82: 48–53.
68 Foss JF, Orelind E, Goldberg LI. Effects of methylnaltrexone on
morphine-induced cough suppression in guinea pigs. Life Sci 1996;
59: PL235–38.
69 Singleton PA, Lingen MW, Fekete MJ, Garcia JG, Moss J.
Methylnaltrexone inhibits opiate and VEGF-induced angiogenesis:
role of receptor transactivation. Microvasc Res 2006; 72: 1–11.
70 Yuan CS, Foss JF, O’Connor M, Osinski J, Roizen MF, Moss J.
Effects of intravenous methylnaltrexone on opioid-induced gut
motility and transit time changes in subjects receiving chronic
methadone therapy: a pilot study. J Pain 1999; 83: 631–35.
71 Zimmerman DM, Gidda JS, Cantrell BE, Schoepp DD, Johnson BG,
Leander JD. Discovery of a potent, peripherally selective
trans-3,4-dimethyl-4(3-hydroxyphenyl) piperidine opioid antagonist
for the treatment of gastrointestinal disorders. J Med Chem 1994;
37: 2262–65.
72 Schmidt WK. Alvimopan (ADL 8-2698) is a novel peripheral opioid
antagonist. Am J Surg 2001; 182: 27S–38S.
73 Goodman AJ, Le Bourdonnec B, Dolle RE. Mu opioid receptor
antagonists: recent developments. ChemMedChem 2007;
2: 1552–70.
74 Neary P, Delaney CP. Alvimopan. Expert Opin Investig Drugs 2005;
14: 479–88.
1206
75 Liu SS, Hodgson PS, Carpenter RL, Fricke JR Jr. ADL 8-2698,
a trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine, prevents
gastrointestinal effects of intravenous morphine without affecting
analgesia. Clin Pharmacol Ther 2001; 69: 66–71.
76 Gonenne J, Camilleri M, Ferber I, et al. Effect of alvimopan and
codeine on gastrointestinal transit: a randomized controlled study.
Clin Gastroenterol Hepatol 2005; 3: 784–91.
77 Barr WH, Nguyen P, Slattery M, Russell R, Carpenter RL.
ADL8-2698 reverses opioid induced delay in colonic transit.
Clin Pharmacol Ther 2000; 67: 91 (abstr).
78 Paulson DM, Kenndy DT, Donovick RA, et al. Alvimopan: an oral,
peripherally acting, μ-opioid receptor antagonist for the treatment
of opioid-induced bowel dysfunction—a 21-day treatment
randomized clinical trial. J Pain 2005; 6: 184–92.
79 Webster L, Jansen JP, Peppin J, et al. Alvimopan, a peripherally
acting mu-opioid receptor (PAM-OR) antagonist for the treatment
of opioid-induced bowel dysfunction: results from a randomised,
double-blind, placebo-controlled, dose-finding study in subjects
taking opioids for chronic non-cancer pain. Pain 2008; 137: 428–40.
80 Taguchi A, Sharma N, Saleem RM, et al. Selective postoperative
inhibition of gastrointestinal opioid receptors. N Engl J Med 2001;
345: 935–40.
81 Wolff BG, Michelassi F, Gerkin TM, et al, and Alvimopan
Postoperative Ileus Study Group. Alvimopan, a novel, peripherally
acting μ opioid antagonist – results of a multicenter, randomized,
double-blind, placebo-controlled, phase III trial of major abdominal
surgery and posterative ileus. Ann Surg 2004; 240: 728–35.
82 Delaney CP, Weese JL, Hyman H, et al. Phase III trial of alvimopan
a novel, peripherally acting, mu-opioid antagonist, for
posteropertive ileus after major abdominal surgery.
Dis Colon Rectum 2005; 48: 1114–29.
83 Viscusi ER, Goldstein S, Witkowski T, et al. Alvimopan, a
peripherally acting mu-opioid antagonist, compared with placebo in
postoperative ileus after major abdominal surgery. Surg Endosc
2006; 20: 64–70.
84 Herzog TJ, Coleman RL, Guerrieri JP, et al. A double-blind,
randomized, placebo-controlled phase III study of the safety of
alvimopan in patients who undergo simple total abdominal
hysterectomy. Am J Obstet Gynecol 2006; 195: 445–53.
85 Kirk L, Enker WE, Delaney CP, et al. Gastrointestinal tract recovery
in patients undergoing bowel resection. Arch Surg 2008;
143: 1098–105.
86 P & T Community. Alvimopan studies halted after cardiovascular
problems reported. http://www.formkit.com/Daily/DailyDetail.
cfm?chosen=65062 (accessed Jan 9, 2009).
87 US Food and Drug Administration. FDA approves Entereg to help
restore bowel function during surgery. http://www.fda.gov/bbs/
topics/NEWS/2008/NEW01838.html (accessed Jan 11, 2009).
88 Herbert MK, Holzer P. Standardized concept for the treatment of
gastrointestinal dysmotility in critically ill patients—current status
and future options. Clin Nutr 2008; 27: 25–41.
89 National Institute for Health and Clinical Excellence. Health
Technology Appraisal: methylnaltrexone for the treatment of
opioid-induced bowel dysfunction in advanced illness or palliative
care. http://www.nice.org.uk/media/851/C6/18BowelDysfunction
DraftScope.pdf (accessed Jan 11, 2009).
90 Beattie DT, Cheruvu M, Mai N, et al. The in vitro pharmacology of
the peripherally restricted opioid receptor antagonists, alvimopan,
ADL 08-0011 and methylnaltrexone.
Naunyn Schmiedebergs Arch Pharmacol 2007; 375: 205–20.
www.thelancet.com Vol 373 April 4, 2009