Alvimopan

Drug Evaluation

10.1517/13543784.14.4.479 © 2005 Ashley Publications Ltd ISSN 1354-3784 479

Ashley Publicationswww.ashley-pub.com

AlvimopanPaul Neary & Conor P Delaney†

†Department of Colorectal Surgery/A-30, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA

Alvimopan is a synthetic peripherally restricted µ-receptor opioid antagonist.Alvimopan has a greater affinity for the µ-receptor than the κ- or σ-opioidreceptors (Ki = 0.77 nM). The polarity of the molecule limits gastrointestinalabsorption and central nervous system penetration. It has limited systemicbioavailability and higher affinity for the µ-opioid receptor than naloxone(Ki = 3.7 nM). Completed Phase III trials suggest efficacy in accelerating therecovery of gastrointestinal function after abdominal surgery. Adverse eventswith all doses have been similar to placebo groups. Further efficacy in allevi-ating opioid-induced bowel dysfunction in patients with chronic opioidusage has also been demonstrated. This evidence-based review assesses thisnew drug and discusses its potential role in clinical practice.

Keywords: ADL-8-2698, alvimopan, Entereg™, opioid antagonist, opioid-induced bowel dysfunction, post-operative ileus

Expert Opin. Investig. Drugs (2005) 14(4):479-488

1. Introduction

Opioid-based analgesia is not the effective panacea of anodynes in controlling post-operative pain that it was once hoped to be. The primary side effects of these medi-cations include sedation and gastrointestinal dysmotility. The most troublesomegastrointestinal symptoms associated with opioid usage include nausea, vomiting,constipation and associated colic-like abdominal pain [1]. These symptoms fallunder the largely under-recognised condition labelled as opioid-induced bowel dys-function (OBD) [2]. Both the acute and chronic usage of opioids may cause OBD.In patients on chronic opioid medication, constipation might become a difficultclinical problem. Furthermore, in patients who have undergone surgery, the dura-tion of the postoperative ileus might be compounded by the necessary use of opioidsfor effective analgesia.

With increasing understanding of the neurokinetics underlying the enteric nerv-ous system, the discovery of the presence of enteric opioid receptors and the clinicalapplication of opioid agonists for the treatment of diarrhoea, attention turned to thepossibility of utilising selective opioid antagonists in an attempt to minimise, oreven reverse, the deleterious gastrointestinal side effects associated with opioid usage.

Opioid receptors are present in the central, peripheral and enteric nervous systems.The clinical use of morphine as an analgesic targets both the central and peripheralµ-receptors. Most gastrointestinal dysmotility associated with the use of morphineappears to be related to its peripheral action. Initial attempts at targeting opioid-related dysmotility involved the use of the pan-opioid receptor antagonist naloxoneand met with some success in alleviating OBD. The efficacy of naloxone for OBDwas compromised due to its limited systemic bioavailability secondary to an extensivefirst-pass metabolism, and the reversal of centrally mediated analgesia [3].

N-Methylnaltrexone is a more selective peripheral quaternary opioid receptorantagonist, with preferential µ-receptor affinity. It represented a significant develop-ment in the search for an effective peripheral opioid antagonist that did not impairthe central receptors necessary for analgesia [4]. N-Methylnaltrexone was the first rela-tively selective peripheral opioid antagonist developed for clinical usage [5]. It is thequaternary derivative of the opioid antagonist naltrexone. The bioavailability of

1. Introduction

2. Gastrointestinal motility

3. Opioid receptors

4. Peripheral opioid antagonists

5. Clinical trials

6. Conclusion

7. Summary

8. Expert opinion

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480 Expert Opin. Investig. Drugs (2005) 14(4)

N-methylnaltrexone is < 1% and it does not cross the blood–brain barrier. N-Methylnaltrexone has been shown in severalclinical trials to reduce the delay in transit time associated withchronic opioid use in a dose-dependent fashion [6].

In recent years, research has focused on newer opioidreceptor antagonists in the form of ADL8-2698 (alvimopan)[7], which is highly selective for the µ-receptor and has beenshown to be safe and effective in clinical trials. The possibil-ity of using alvimopan to reduce postoperative ileus is anarea of rapidly developing interest. This review provides anoverview of alvimopan: a novel selective peripherally actingopioid-receptor antagonist.

2. Gastrointestinal motility

Alvimopan acts on the pathways that influence gastro-intestinal motility in the postoperative period. The regulationof these pathways includes the inherent activity of the entericnervous system, which is reflected in the electrophysiologicalactivity of the smooth muscle cells by both slow waves andpropulsive spikes. The pacemaker potentials are a complexmixture of hormonal interactions, input from the autonomicnervous system and a series of neuronal reflexes that mightinduce the activation or inhibition of gut motility [8].

The enteric nervous system is enclosed within the bowellayers itself and is composed of a myenteric plexus locatedbetween the longitudinal and circular layers of smooth muscleand a submucosal plexus. The latter is concerned with localcontrol of secretions and absorption. The myenteric plexusoccupies the length of the intestine and is involved in conduc-tion velocity, contraction rhythm and mural tone [9]. Thelarge array of neurotransmitters implicated in the activity ofthe nervous system includes acetylcholine, noradrenaline,dopamine, 5-hydroxytryptamine (5-HT), vasoactive intestinalpeptide, substance P, leu-enkephalin and met-enkephalin.Knowledge of the impact of these neurotransmitters on gas-trointestinal function has allowed several clinically usefulagents that augment gastrointestinal motility to be developedsuch as domperidone and cisapride.

The autonomic nervous system is also intricatelyinvolved in the control of gastrointestinal motility; para-sympathetic input is mediated through the vagus and pel-vic nerves. The vagus nerve extends from the oesophagusto the proximal colon, while the sacral parasympatheticnerves (S2, -3 and -4) influence the remaining colon. Theneurons are located in the myenteric and submucosalplexus, and activation induces increased gastrointestinalmotility. The sympathetic nerve fibres between T5 and L2through the splanchnic nerves also synapse with neurons ofthe myenteric plexus and are inhibitory in nature [10].Gastrointestinal hormones such as gastrin, cholecystoki-nin, motilin, somatostatin, glucagons and gastric inhibi-tory peptide also influence motility. This multitude makesit difficult to define the exact significance of each agent inthe overall control.

Endogenous opioids, such as met-enkephalin, leu-enkepha-lin, endomorphin, dynorphin and β-endorphin, are alsopresent in the neurons of the enteric nervous system. Theseendogenous opioids have been detected in the neurons of themyenteric plexus, submucosal plexus and the endocrine cellsof the intestinal mucosa [11]. The activity of these endogenousopioids is dependent on the specificity and affinity for the var-ious membrane-bound opioid receptors described. They havebeen shown to activate receptors in the central nervous, gas-trointestinal, musculoskeletal and vascular systems and sen-sory peripheral neurons [12]. Opioid analgesics are not asspecific for the endogenous opioid receptors as their naturallyoccurring counterparts. However, a better understanding ofthe differential distribution and functionality of the variousopioid receptors has provided a sound rationale for targetingthese receptors in clinical practice. By using selective opioidreceptor agonists and, more recently, selective opioid antago-nists in the control of gastrointestinal and analgesic pathways,significant improvement in the maintenance of gut motilityhas been achieved without compromising analgesia.

3. Opioid receptors

There are three main types of opioid receptors recognised, theκ-, σ- and µ-opioid receptors, respectively [13]. However, thereare further receptors in this family, but only limited work hasbeen performed on their functionality. These include theε-receptor and OP4 receptor [14,15]. The classic three opioidreceptors (κ-, σ- and µ-) bind endogenous ligands thatinclude endorphins, enkephalins, dynorphins and therapeuticexogenous ligands such as morphine and its derivatives. Theκ-opioid receptor has been shown to induce analgesia, boweldysfunction, diuresis and sedation. Most of these effects havebeen demonstrated using the opioid dynorphin A(1-13).There are also a number of κ-opioid receptor subtypes, buttheir function is poorly understood [16]. The κ-opioid recep-tors are located in the intestinal wall, primarily in the mye-nteric plexus and have been shown to be present on both thenerve terminals and on the somatodendritic synaptic terminalelements. They have been shown to be present in the CNSand are involved in analgesia with the enkephalins as theirendogenous ligand.

Of the described subtypes, the µ-opioid receptors are pri-marily implicated in regulating analgesia and gastrointestinalmotility. The µ-opioid receptor may be further classified intothe subtypes -µ1 and -µ2. The endogenous opioids, endomor-phin-1 and -2 have the highest affinity for the µ-opioid recep-tor; however, it is β-endorphin that has the most efficacy interms of action. The µ1-receptors are located in the brain andtheir activation is responsible for analgesia. These receptorsare the target of morphine and most clinically used opioid-based analgesic agonists. The µ2-receptor is present in the spi-nal cord and gastrointestinal tract. The µ-receptors are partic-ularly dense in the bowel wall with the µ-receptor identifiedin the submucosal and mucosal layers in rat models. They are

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also present in the muscle layer, being identified on nerve ter-minals. Activation of these receptors is responsible for respira-tory depression and OBD [17]. The µ1- and µ2-receptors are aproduct of the MOR1 gene. The difference is establishedbased on two splice variants of the presence or absence ofeight C-terminal amino acids. In animal models, morphinedecreases acetylcholine release through the activation of theµ-receptors. This decrease in neurotransmitter release (acetyl-choline) results in a reduction in gut motility. In patientsreceiving morphine, myoelectrical colonic activity is disruptedfollowing surgery [18]. With progressive opioid dose escala-tion, the gastrointestinal side effects increase, includingdecreased colonic propulsion, increased sphincter tone, gas-trostasis and increased fluid absorption [19]. As the currentopioid based analgesics remain nonselective for the variousopioid receptor subtypes, the manifestations of OBD oftenparallels the efficacy of analgesia achieved in clinical practice.

The ideal paradigm is, therefore, to maximise the efficacyof opioid-induced analgesia without having adverse gastro-intestinal side effects. This paradigm is complicated becausemorphine-induced gastrointestinal delay has been shown tobe mediated by its central agonist and peripheral agonistopioid receptor effect.

4. Peripheral opioid antagonists

Two approaches were used to develop an effective therapeuticstrategy to ameliorate the gastrointestinal side effects of opio-ids without compromising analgesia. The first attempted tolimit the systemic absorption of effective opioid antagonistsand the second the use of selective peripheral opioid receptorspecific antagonists while limiting its ability to cross theblood–brain barrier.

Naloxone (a specific µ-receptor antagonist) has been shownto reverse OBD. This antagonist has an extensive first-passmetabolism and results in an oral bioavailability of 2%. Unfor-tunately, clinical trials have demonstrated a narrow therapeuticindex due to the possible triggering of analgesia reversal or sys-temic opioid withdrawal [20]. Furthermore, a variable efficacy indosage among individual patients limits its clinical use [21]. Sim-ilarly, nalmefene, a nonselective µ-receptor antagonist workinglargely through its metabolite nalmefene glucuronide, has notbeen shown to be clinically effective in ameliorating OBDwithout compromising analgesia [22].

The second approach of limiting how the antagonist crossesthe blood–brain barrier, thereby concentrating its binding effi-cacy to the peripheral µ-receptors, is a more promising area ofresearch. The first drug in this category is the nonselectiveµ-receptor antagonist methylnaltrexone [23]. Naltrexone is a ter-tiary opioid receptor antagonist and is lipid soluble. This allowsit to cross into the CNS and inhibit the efficacy of morphine.The quaternary derivative of naltrexone is methylnaltrexone.This has been shown to be poorly lipid soluble, does not crossinto the CNS and does not antagonise the central analgesiceffects of morphine. This quaternary derivative is also relativelyresistant to demethylation to the tertiary form [24]. However, itis a non-selective opioid receptor antagonist and the efficacy ofthe drug is due to restriction of its activity to peripheral sites ofaction. Clinical trials have demonstrated that methylnaltrexonereverses OBD without reversing analgesia [25], is effective inenteric oral form [26] and may be used in patients on chronicopioid agonists (methadone-maintenance programme) withequal efficacy to methadone [127]. It is also available in intrave-nous form. The absorption following oral administration is< 1 % and, although nonselective for the µ-receptors, it isconsidered to be a µ-receptor preferred antagonist.

Following the demonstration that peripherally restrictedopioid antagonists could be clinically successful, the develop-ment of a more selective peripheral µ-receptor antagonist withlimited CNS action became the focus of research. This led tothe development of a compound known as alvimopan(LY-246376; ADL 8-2968).

4.1 Biochemistry of alvimopanAlvimopan was developed as a peripherally acting µ-receptorantagonist. It has a molecular weight of 461 kDa. It is a com-pletely synthetic molecule with a large molecular weight and azwitterionic form (C25H32N2O4.2H2O). This polarity limitsits gastrointestinal absorption and CNS penetration. Thesynthesis of alvimopan is a 12-step process from 1,3-dime-thyl-4-piperidone with a yield of 6.2%. The key reaction isthe cis-thermal elimination of a carbonate from an alkaloid at190°C, with the key intermediate being the production of(3R-4R)-3-(3,4-dimethyl-4-piperidinyl)phenol. The systemicoral bioavailability is maintained by the size of a nitrogen sub-stitution that augments the µ-receptor antagonist and restrictsthe penetration of the blood–brain barrier. The resultingcompound is trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperi-dine [28]. Synonyms and analogues include ADL-01-0160,ADL-01-0161, ADL-8-2698 and LY-246736 labelled as (±)-([2(S)–[(4[R]–(3-hydroxyphenyl)-3[R]4–dimethyl-1-piperid-inyl)-methyl]1-oxo-3-phenylpropyl]-amino) acetic aciddehydrate (Figure 1).

4.2 Pharmacology and kinetics of alvimopanAlvimopan has a greater affinity for the µ-receptor than forthe κ- or σ-opioid receptors. This translates as an inhibitoryconstant (Ki) of 0.77 nM for the µ-opioid receptor versus40 (κ-) and 4.4 nM (σ-), respectively, for the other types

N

OH

O

NH

OH

O

2H2O

Figure 1. Chemical structure of alvimopan.

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[29,30]. Furthermore it does not demonstrate affinity for themain non-opioid receptors including adrenergic (α1-, α2-,β-), dopaminergic (D1, D2), 5-HT2, histamine (H1), GABA,benzodiazepine or muscarinic receptors. It also demonstrates ahigh affinity for the µ-opioid receptor relevant to the bindingof naloxone (Ki = 3.7nM).

4.3 BioavailabilityAlthough essentially a peripherally acting µ-opioid antagonist,alvimopan may cross the blood–brain barrier at very highconcentrations in some animal species. This permits thereversal of the centrally mediated analgesic action of mor-phine consistent with other drugs in this class. The peripheralaction, however, is preferential due to its high affinity for theµ-opioid receptor and the polarity of the nitrogen substitutethat limits central mediation. Intravenous administrationinhibits the peripheral µ-opioid receptors 200-fold more thanthe central µ-receptor. In animal studies, restoration of bowelfunction occurred in 50% of mice (1.1 mg/kg p.o.) as evi-denced by the onset of diarrhoea in morphine-dependentmice [27]. The absence of central antagonism was demon-strated in the mouse charcoal meal-test with alvimopanreversing morphine-induced constipation for > 8 h without aclinical manifestation of morphine withdrawal. This demon-stration of the efficacy of oral administration of alvimopanwas twice the dose calculated for achieving the same resultusing naloxone.

4.4 Metabolism, distribution and clearance of alvimopanThe intravenous administration of alvimopan results in adose-dependent increase in plasma concentration. In dogs andrabbits, the serum half-life is reported as 10 min. Tracer[14C]-alvimopan studies demonstrate minimal distribution ofthe drug in the blood compartment or sites other than theµ-receptor; in particular, this includes the cerebral tissue.There is no evidence of plasma compartment accumulationand systemic metabolism is considered to be hepatic in origin.The oral bioavailability is poor as reflected by poor systemicabsorption and oral doses of < 100 mg/kg in a canine modelproduced low plasma levels (mean maximal concentration[Cmax] = 92.9 ng/ml).

The oral bioavailability is of the order of 0.03%. Suchpoor systemic bioavailability does not indicate a lack of effi-cacy, as oral administration produces high levels of clinicalgastrointestinal activity. The restricted distribution of alvi-mopan in animal models has also been confirmed using[14C]-alvimopan whole-body autoradiography in rats usingboth oral and intravenous administration. This showed asparing of the brain and spinal cord in rats treated with alvi-mopan consistent with its peripheral selective binding. In arat model following oral dosage of [14C]-alvimopan200 mg/kg demonstrated a portal plasma concentration of140 ng equivalents of 14C/ml at 1 hour whereas the meanpeak plasma concentration was only 20.5 ng/ml [27]. These

findings are consistent with significant first-pass hepaticmetabolism. The excretion pathway of the drug has beenassessed using [14C]-alvimopan following both oral andintravenous administration. The urinary excretion is 0.4%(oral ingestion) and 22% (intravenous administration). Thebiliary excretion is 15% of the administered dose regardlessof the method of administration. In animal studies, therehas been no significant toxicity. These have used dosageschedules of ≤ 500 mg/kg for mice and 20 mg/kg i.v. forrats. The long-term safety assessment for a period of6 months in both canine and rat models did not demon-strate any acute toxicity. However, the studies did notaddress any fertility or teratogenic long-term outcomes.

5. Clinical trials

Successful application in animal models has led to the pro-gressive introduction of this new peripheral opioid receptorantagonist to the clinical arena. To date, alvimopan has com-pleted Phase I, II and III clinical trials. The clinically relevanttherapeutic target population consists of patients with OBD;this includes those on chronic opioid medication and poten-tial amelioration of postoperative ileus. The Phase II clinicaltrials have largely focused on assessing the role of alvimopanin shortening the period of postoperative ileus incurred inpatients after major abdominal surgery.

5.1 Postoperative ileusThe transient period of enteric inertia after abdominal surgeryis termed postoperative ileus. This is a variable period of cessa-tion of bowel function. It appears mandatory followingabdominal surgery but also occurs after other procedures. Todate, the exact criteria for defining postoperative ileus asregards onset, duration and resolution of symptoms have notbeen agreed on by any consensus group. Apart from the surgi-cal procedure itself, a major factor that is considered to con-tribute to the development of postoperative ileus is theprescription of exogenous opiates [31]. It is clear that, aftermajor abdominal surgery, there is a period of initial bowelinertia and this translates into an enforced delay in discharg-ing patients from hospital after their surgery. The extent ofpostoperative ileus combined with postoperative pain,mechanical factors, such as drains and postoperative fatigueall combine to extend the average postoperative stay after sur-gery to between 5 and 10 days in most reported series [32].The direct result of this prolonged hospital stay is seen infinancial terms of an estimated $1.75 billion for 1.8 milliondays spent in hospital in the US [33].

Attempts to ameliorate the duration of postoperative ileushave been undertaken by several units and together consti-tute the concept of ‘fast-track care pathways’ for expeditingrecovery after surgery. These protocols involve early ambula-tion, early feeding, early transfer to oral-based analgesia, andearly removal or absence of nasogastric tubes, drains andurinary catheters. Using an aggressive postoperative care

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plan of accelerated rehabilitation, Basse et al. were able todecrease their median length of stay from 8 days down to2 days for patients undergoing open major abdominal sur-gery [34]. This prospective case control study used retrospec-tive case controls and utilised epidural analgesia as part oftheir protocol. The efficacy of epidural analgesia in shorten-ing the duration of postoperative ileus have been somewhatsupported by a Cochrane report [35], although the studiesused for this meta-analysis did not include fast-track carepathways. Similar results of shortening the length of stay byadopting a ‘fast-track’ postoperative management plan havebeen shown in the absence of epidural analgesia in otherunits and, therefore, one must be aware of the independentbenefits of this approach when interpreting the data fromthe alvimopan clinical trials [36]. Furthermore, in these trials,the study end points of ‘time to first bowel motion’ and‘time to hospital discharge’ must be viewed in the context ofclinical relevance for the patient. Any improvements in therapidity of clinical recovery must, therefore, translate intoboth a clinically relevant impact, as well as a financiallymeaningful alteration in postoperative outcome. Ultimately,this should be reflected in a reduced length of hospital stayfor the patient or a reduction in other complications.

In all of the Phase III clinical trials that addressed theeffect of alvimopan on postoperative ileus, the baseline carein both placebo and treatment groups was similar to a ‘fast-track’ postoperative-care programme. The control group andthose that received oral alvimopan received postoperativeintravenous patient-controlled analgesia and had theirnasogastric tube removed at the end of surgery or within thefirst postoperative day. They commenced liquids on the firstpostoperative day and were offered solid food by day 2 usingstandardised criteria and orders for advancement of diet.These components constitute an accelerated postoperativecare pathway, and any reduction in the length of hospital stayas a result of this approach should be equally applicable tothe treatment and control groups based on the double-blindrandomised construct of the trials.

5.2 Phase I trialsThree Phase I trials were undertaken using oral doses of alvi-mopan. The first was a double-blind placebo-controlledcrossover trial. A total of eight subjects (males 28 – 54 years)were placed on loperamide (opioid agonist; 8 mg), whichresulted in constipation (p < 0.01). The colonic transit timewas assessed using serial radio-opaque marker screening. Thevolunteers then received alvimopan at 2.4 or 24 mg t.i.d.over 4 days. The study demonstrated the reversal or blockadeof the loperamide-induced decrease in colonic transit timewith both dosing schedules [37]. In a second randomised, pla-cebo-controlled, double-blind crossover study 13 healthy vol-unteers were assessed [38]. Alvimopan 3 mg p.o. t.i.d. for4 days reversed morphine (30 mg b.i.d.)-induced colonichypomotility as measured by radio-opaque marker screenedcolonic transit time (p < 0.05). The third study assessed oral

cecal transit time in 14 healthy volunteers using a 4-mg oraldose [39]. This was a double-blind crossover study. The doseof morphine used was 0.05 mg/kg and volunteers weretreated as follows: oral and intravenous placebo; oral placeboand intravenous morphine; and alvimopan 4 mg p.o. andintravenous morphine. The drug once again reversed themorphine-induced delay in enteric transit time (p < 0.006).The study also noted an absence of reversal of morphine-induced central effects using 45 further postoperativepatients in a double-blind fashion. There was no reversal ofmorphine-induced pupillary constriction and efficacy ofanalgesia. This trial had equal sex distribution in volunteersand the oral cecal transit time was assessed using lactulose/hydrogen breath tests. The end result was a reduction of tran-sit time from a prolongation with morphine of 103 min tonear baseline. The manuscript concluded that alvimopanprevents morphine-induced increases in gastrointestinal tran-sit time by means of selective peripheral opioid antagonismwithout affecting central opioid analgesia.

5.3 Phase II trials5.3.1 Chronic opiate-use studiesTwo studies were conducted to assess the efficacy of alvimopanin patients with chronic opioid usage. The first enrolled75 patients to assess safety and efficacy of alvimopan withincreasing doses. A single dose was used in a dose-escalatingfashion using alvimopan (0.5, 1.5 and 3 mg). The patients tar-geted had documented OBD. The patients were administeredplacebo or alvimopan and it was demonstrated that the vol-ume of stool, duration of onset to first stool and incidence ofdry hard stools were all decreased in those receiving alvimo-pan. The onset of action was as rapid as 6 h after commencingtreatment. Notably, in those receiving the highest dose of alvi-mopan, 11 patients withdrew due to gut-specific withdrawalsymptoms. A second study assessed the dose efficacy and safetyof alvimopan in 26 patients with chronic opioid usage. Thisused increasing levels of alvimopan over 4 days (0.5, 1.5, 3 and4.5 mg). Again, the efficacy of alvimopan was demonstratedwith patients having an increased stool volume over controlsfor the first 4 days of treatment. In this study, there was nonegative impact seen on analgesia or evidence of the onset ofsigns of opioid withdrawal. The maximum response was seenwithin 4 h of the 3-mg dose and 7 h of the lowest (0.5-mg)dose. In these studies, some patients at the 3-mg dose reportedloose stools, diarrhoea and cramps. In a further preliminarydose-escalation study of seven volunteers, one subject hadincreased bowel frequencies after 0.25- and 1-mg doses of alvi-mopan. This cramping pain lasted 3.25 h and the subject waswithdrawn from further treatments.

5.3.2 Postoperative ileusThe efficacy of alvimopan in ameliorating postoperativeileus was assessed in a randomised, double-blind placebo-controlled study of 78 patients undergoing segmental colonresection or abdominal hysterectomy [40]. The study assessed

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the impact of alvimopan on postoperative gastrointestinalfunction and the length of postoperative hospital stay.Patients received one capsule of alvimopan 1 or 6 mg or anidentical placebo capsule 2 h before abdominal surgery andthen twice daily until the first bowel movement or until dis-charge from the hospital up to a maximum of 7 days. Therewere 26 patients in each group and blinded observersassessed the outcomes. This study demonstrated that thoseadministered alvimopan 6 mg had a significantly earlieronset of the passage flatus (reduced from 70 to 49 h,p = 0.03) and first bowel motion (from 111 to 70 h,p = 0.01), and a decrease in length of hospital stay (from 91to 68 h, p = 0.03). The authors concluded that alvimopanspeeds recovery of bowel function and shortens hospitalisa-tion of patients undergoing abdominal surgery. Althoughthe results were clearly impressive, one of the main criticismsof this paper is the nature of the surgery involved; thepatients had undergone partial colectomy (n = 15), simplehysterectomy (n = 37) and radical hysterectomy (n = 26). Asreflected by the nature of the surgery, nearly all the patientswere female (n = 72). A total of four patients taking the pla-cebo withdrew, as did eight patients receiving alvimopan(1 mg) capsules. Nevertheless, the patients receiving the6-mg capsules had significantly improved outcome scores,with less nausea and time to hospital discharge.

5.4 Phase III trialsAlvimopan has now completed four Phase III trials(14CL302, 14CL306, 14CL308 and 14CL313) assessing itsuse in the restoration of bowel function in patients havingundergone major abdominal surgery. Some caution should benoted in the interpretation of these results because, to date,only 14CL313 has been formally published in the scientificliterature. 14CL302 is also discussed as it is in press and hasbeen presented at a national scientific meeting. There has alsobeen one completed Phase III trial assessing the efficacy ofalvimopan in the treatment of OBD in patients takingchronic opioid medications (13CL304).

5.4.1 Chronic opiate-use studiesThe OBD Phase III trial (OBD 13CL304) enrolled168 patients and examined the efficacy of alvimopan onOBD. These were patients that had chronic use of opioids,such as morphine and codeine, with documented adversebowel function as a result of their opioid ingestion. Thedosing schedule was alvimopan 0.5 or 1 mg or placebodaily for 21 days. The patients were then assessed withregard to the number and frequency of bowel motionsrecorded within the first 8 h of receiving alvimopan com-pared with placebo. The results demonstrated that 43% ofpatients receiving alvimopan 0.5 mg had a bowel motionwithin 8 h; a result that was significant versus placebo(p < 0.001). For those receiving 1 mg, the result was simi-lar with 55% having early bowel motion versus 29% withplacebo (p < 0.001).

5.4.2 Postoperative ileus14CL302 is a double-blind, placebo-controlled trial cur-rently in press. This was a multi-centre study and enrolled451 patients prior to surgery. The primary aim of the studywas to assess the efficacy of alvimopan in postoperative recov-ery of bowel function. The surgery involved was abdominalhysterectomy (30% of patients) or a segmental bowel resec-tion (70%). There were three groups; placebo (n = 153), alvi-mopan 6 mg (n = 152) and 12 mg (n = 146). The patientsreceived the study medication 2 h prior to surgery and twicedaily thereafter for a maximum of 7 days. The primary endpoint of the study was the return of bowel function, whichwas defined as “the later of the following two events: timethat the patient first tolerated solid food (recovery of uppergastrointestinal function), and the time that the patient firstpassed either flatus or a bowel movement (recovery of lowergastrointestinal function)”. In the 6-mg group, this was amean of 86.2 versus 100.3 h for those receiving placebo. Thiswas significant compared with controls (Cox proportionalhazard model: hazard ratio 1.47, p = 0.058). In those receiv-ing the 12-mg dose, a statistical significance was notachieved; however, the study did show a positive trend overplacebo (p = 0.0.58), with a similar reduction in hours. Themost frequently reported adverse side effects were nausea,vomiting and abdominal distension, without any increase inthe placebo group (Table 1).14CL313 was a double-bind, placebo-controlled, multi-cen-tre trial to assess the efficacy of alvimopan on ameliorating theeffects of postoperative ileus, primarily in patients undergoingsegmental bowel resection [41]. The study enrolled510 patients, of which 469 patients participated. As in theother studies, patients received placebo, or alvimopan 6 or12 mg 2 h prior to surgery and twice daily until discharge ora maximum of 7 days after surgery. The composition of theplacebo- and alvimopan-treated groups were similar. The sur-gery involved was abdominal, being either segmental bowelresection (96% of patients) or radical hysterectomy (4%). Ofthose having a bowel resection, the resection was of smallbowel in 9.2% of those receiving placebo, 16.4% of those thatreceived alvimopan 6 mg and 16.7% of the 12-mg alvimopangroup. As defined in prestudy criteria, patients needing astoma because of intra-operative findings were excluded, aswere those with epidurals and cases where a nasogastric tubewas left in situ postoperatively. These patients did remain inthe study for assessment of adverse events, due to the preoper-ative dose received. The study group included those undergo-ing colon and rectal cancer surgery as well as surgery forinflammatory conditions such as Crohn’s disease and diver-ticulitis. The final three groups numbered placebo (n = 149),alvimopan 6 mg (n = 155) and 12 mg (n = 165). The sex dis-tribution was equal in this study. In the 6-mg group there wasa mean difference in return to bowel function of 14.6 h,which was significant from placebo (hazard ratio 1.28,p < 0.05). In the 12-mg group, again there was a significantlyearlier return of bowel function (mean difference 22 h, hazard

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ratio 1.54, p < 0.01) (Figure 2). In both treatment groups astatistically significant earlier return to tolerating solids wasobserved. Interestingly more patients discontinued treatmentwith placebo than with alvimopan for adverse effects such asnausea, vomiting and hypotension.

In both of these studies (14CL302, 14CL313), the mostcommon adverse events were nausea and vomiting. There wereno significant differences for these main adverse effects betweenthe treated and control groups. Noticeably, the overall trendwas to have increased gastrointestinal problems with placebo. Inthe 14CL302 study, serious adverse events were encountered in12.5% of patients; this included 28 patients in the placebogroup: 13 in the 6-mg-treated group and 15 in the 12-mg-treated group. There were three mortalities in this study, noneof which were considered to be related to the study protocol. Inthe 14CL313 study, only two (1.2%) patients in the placebogroup, five (3%) patients in the alvimopan 6-mg group, and nopatients in the 12-mg group had serious adverse effects.

14CL306 enrolled 519 patients to assess the safety and effi-cacy of alvimopan for the amelioration of postoperative ileus.14CL308 is the largest of the studies to date and also aimed toassess the efficacy of alvimopan in ameliorating gastrointesti-nal dysfunction in the postoperative patient; 666 patientswere enrolled. The results were presented by Adolor Corpora-tion in a public release, but have yet to be formally publishedin a scientific journal.

In summary, three Phase III trials assessing the efficacy ofalvimopan in postoperative ileus and one assessing dosage

safety have been completed. When all studies are considered,> 2000 patients have been evaluated. The results show that thedose of 6 mg results in a significantly earlier return of gastroin-testinal function after major abdominal surgery (14CL302 and14CL313). Patients receiving alvimopan 12 mg had an earlierreturn of bowel function in two studies (14CL313) and a posi-tive trend in the third (14CL302, p = 0.11). The Phase III trialassessing safety (14CL306) demonstrated good tolerance ofalvimopan using the 12-mg dose, with 93% of patients com-pleting the study. The remaining Phase III study (14CL304)assessed the efficacy of alvimopan in treating OBD in patientswith a history of chronic opioid usage. This Phase III trial alsoshowed significant benefit in restoration of gastrointestinalfunction in these patients. To date, complications have notbeen reported as being more frequent in a treatment groupcompared with patients receiving placebo.

6. Conclusion

Over the past decade, there has been a progressive evolutionof standardised postoperative care plans in treating patientswho have undergone major abdominal surgery. These evi-dence-based changes have attempted to reduce the magni-tude of the gastrointestinal and systemic insult followingabdominal surgery in order to expedite patient recovery andoutcome. The absence of nasogastric tube placement aftersurgery in a meta-analysis of 26 trials has been shown todecrease postoperative morbidity but not decrease

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Cox proportional hazard model comparisons:6 mg versus placebo: hazard ratio = 1.28, p < 0.0512 mg versus placebo: hazard ratio = 1.54, p < 0.01

Figure 2. Cumulative proportion of patients in the modified intent-to-treat population achieving recovery ofgastrointestinal function over the 10-day postoperative period. Cox model estimates. Reproduced with permission from thepresenter, from: DELANEY CP, WEESE JL, HYMAN NH: Prospective, randomised, double-blind, multicentre, placebo-controlled study ofalvimopan, a novel peripherally-acting µ-opioid antagonist, for postoperative ileus after major abdominal surgery (Study 14CL302). Dis.Colon Rectum (2005) (In Press).

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postoperative ileus [42]. Early ambulation, early feeding,restriction of intraoperative fluids, use of epidural anaesthesiaand gum chewing have all been incorporated into acceleratedpostoperative care pathways [43,44]. Using these postoperativecare programmes, the mean length of stay for a patientundergoing major abdominal surgery may be reduced to3.5 – 5.5 days [42,45]. Furthermore, patients undergoinglaparoscopic colorectal surgery, combined with a ‘fast-track’postoperative care programme, may have their mean lengthof stay reduced to < 3 days [46].

In both the 14CL302 and 14CL313 trials, the mean lengthof stay (‘hospital discharge order written’) for the patients thatwere treated with placebo ranged from 5.08 (14CL302) to6.08 days (14CL313). The introduction of alvimopan wasable to reduce this ‘time to writing hospital discharge order’by a range of 7.2 – 20 h, depending on the dose used andpatient population being studied. The mixed surgical popula-tion (simple hysterectomy, radical hysterectomy, colonic, rec-tal and small bowel resections) may be an explanatory factorfor these differences in outcome.

A meta-analysis of the studies performed to date examiningoutcomes related to specific indications for surgery (bowelresection versus hysterectomy) has not been reported. Theresults of this may help direct optimal clinical use of this agent.

Finally, the efficacy of alvimopan in reducing the length of stayin hospital has not been studied in the setting of laparoscopiccolorectal surgery, and this will probably not be evaluated untilafter approval of the medication by the FDA.

7. Summary

Alvimopan represents the first orally available, peripherallyrestricted opioid antagonist that successfully demonstratesperipheral µ-receptor selectivity. The drug has completed fivePhase III clinical trials enrolling > 2000 patients. The drugseems to have good tolerance without any evidence of seriousadverse side effects, and a reduction in side effects over thatseen with placebo. Clinical efficacy of early restoration ofgastrointestinal function in patients following surgery and inthose with a history of OBD has been demonstrated. No long-term clinical studies on toxicology, tolerance and teratogenicityare currently available.

8. Expert opinion

Delayed restoration of gastrointestinal function in the post-operative period has significant healthcare and economicimplications. The development of postoperative ileus was

Table 1. Most common treatment-emergent adverse events (all grades) occurring in ≥ 10% of patients in any treatment group by frequency: safety population.

n (%)

Preferred term Placebo(n = 153)

Alvimopan 6 mg(n = 150)

Alvimopan 12 mg(n = 146)

Nausea 104 (68) 96 (64) 86 (58.9)

Vomiting NOS 49 (32) 38 (25.3) 22 (15.1)*

Abdominal distension 24 (15.7) 17 (11.3) 24 (16.4)

Headache NOS 18 (11.8) 24 (16) 17 (11.6)

Hypotension NOS 23 (15) 18 (12) 17 (11.6)

Pruritus NOS 15 (9.8) 20 (13.3) 17 (11.6)

Pyrexia 19 (12.4) 18 (12) 15 (10.3)

Hypertension NOS 14 (9.2) 19 (12.7) 18 (12.3)

Insomnia 23 (15) 13 (8.7) 15 (10.3)

Tachycardia NOS 15 (9.8) 17 (11.3) 14 (9.6)

Constipation 22 (14.4) 12 (8) 10 (6.8)‡

Flatulence 17 (11.1) 12 (8) 13 (8.9)

Dyspepsia 16 (10.5) 8 (5.3) 15 (10.3)

Postoperative ileus 11 (7.2) 15 (10) 11 (7.5)

Diarrhoea NOS 16 (10.5) 12 (8) 8 (5.5)

Data from 14CL302, outlining side effects of patients treated with alvimopan. Reproduced with permission from the authors, from: DELANEY CP, WEESE JL, HYMAN NH: Prospective, randomised, double-blind, multicentre, placebo-controlled study of alvimopan, a novel peripherally acting µ-opioid receptor antagonist, for postoperative ileus after major abdominal surgery (Study 14CL302). Dis. Colon Rectum (2005) (In Press).*p < 0.001 Using a two-sided Fisher’s exact test in comparison with placebo. ‡p = 0.04 Using a two-sided Fisher’s exact test in comparison with placebo. NOS: Not otherwise specified.

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estimated as costing $750 million in 1986 to the US health-care system [47]. Attempts to reduce this period of gastro-intestinal dysfunction have included the use of prokinetics(erythromycin and metaclopromide) and nasogastric intuba-tion, but have met with little success [48,49]. The introductionof laparoscopic colorectal surgery, early postoperative feeding,the use of thoracic epidural analgesia and perhaps even chew-ing gum have already demonstrated an improvement in theearly restoration of gastrointestinal function [50]. These diverseapproaches outline the complexity of factors involved in theonset and resolution of postoperative bowel dysfunction. Alvi-mopan has been introduced as a prototype selective µ-opioidreceptor antagonist. The therapeutic rationale of selectivelyinhibiting the deleterious gastrointestinal effects of opioids,whether from the inherent postoperative endogenous opioidsurge or that of exogenous opioid administration, has beenborne out by successful Phase III trials.

It remains unclear at present what impact the addition of alvi-mopan may have in the setting of a multimodality approach topostoperative care, including early introduction of diet, laparo-scopic surgery, and with or without epidural-based analgesia,‘gum chewing’ and fluid restriction. It is probable that the effectwill mirror those seen in the Phase III studies, as all study patients(including placebo) were maintained on fast-track type pathways.

As alvimopan is an opioid antagonist, the efficacy of res-toration of gastrointestinal function in patients with OBDis both practical and highly encouraging. Two remainingissues relating to the introduction of alvimopan for postop-erative ileus include deciding on a 6- or 12-mg dose, andthe cost of treatment. Continuing analysis of all trialresults will help decide the optimum dosing protocol andthe most suitable patients for use. The final cost of theproduct will determine how this drug can be most effec-tively integrated into postoperative care plans followingabdominal surgery. Nevertheless, alvimopan is a very excit-ing product as the first of its type, which offers real clinicalimprovements without serious adverse events. Furtherstudies will determine the role of this medication for thoseundergoing laparoscopic bowel surgery, or those requiringa stoma; groups that have not been evaluated to date.

Although the Phase III trial completed that addressedOBD was relatively small in number, the potential for thisnew drug is promising. Alvimopan is the only selective µ-opi-oid receptor antagonist to have completed Phase III efficacytrials and, as such, represents the first in a hopefully new gen-eration of well-tolerated, peripherally restricted µ-opioidreceptor antagonists that will have significant impact bothclinically and on an economic healthcare basis.

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AffiliationPaul Neary1 & Conor P Delaney MCh PhD FRCSI (Gen)2†

†Author for correspondence1Department of Colorectal Surgery and Minimally Invasive Surgical Center, Cleveland Clinic Foundation, Cleveland, OH, USA2Department of Colorectal Surgery/A-30, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, OH, USATel: +1 216 445 1647; Fax: +1 216 445 8627;E-mail: [email protected]

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