Opioid-Induced Bowel Dysfunction

Vol. 35 No. 1 January 2008 Journal of Pain and Symptom Management 103

Review Article

Opioid-Induced Bowel DysfunctionJay Thomas, MD, PhDSan Diego Hospice & Palliative Care and University of California, San Diego, San Diego,

California, USA

AbstractOpioid-induced bowel dysfunction is a distressing condition that may persist indefinitely inthe clinical setting. As we understand more about normal gastrointestinal (GI) physiology,we are also beginning to understand more fully how opioids cause bowel dysfunction.Current therapeutic interventions for opioid-induced bowel dysfunction can be burdensomeand sometimes lack efficacy. Systemic opioid antagonists administered orally can inducelaxation, but can unpredictably induce systemic or local GI tract withdrawal symptoms. Twonew investigational agents, alvimopan and methylnaltrexone, are peripherally acting opioidantagonists that do not cross the blood-brain barrier. Studies to date show promise that theseagents may relieve opioid-induced bowel dysfunction in a well-tolerated manner withoutreversing central analgesia. J Pain Symptom Manage 2008;35:103e113. � 2008 U.S.Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

Key WordsOpioid, constipation, alvimopan, methylnaltrexone

IntroductionOpioids are commonly used to treat pain

and dyspnea. However, their efficacy is accom-panied by burdensome side effects, the mostfrequent being nausea, cognitive impairment,and bowel dysfunction. Empirically, tolerance,which is still not well understood, developsquickly to most opioid-induced side effects.Unfortunately, tolerancedif it occursdoftenis unable to reverse the clinically significantadverse effects known generically as opioid-induced bowel dysfunction. This may lead totremendous suffering in many patients and is

Graphics are courtesy of Upside Endeavors, LLC.

Address correspondence to: Jay Thomas, MD, PhD, SanDiego Hospice & Palliative Care, 4311 3rd Avenue,San Diego, CA 92103, USA. E-mail: [email protected]

Accepted for publication: January 27, 2007.

� 2008 U.S. Cancer Pain Relief CommitteePublished by Elsevier Inc. All rights reserved.

magnified in patients with advanced illnesswho may be facing the end of life. Patientssometimes consider decreasing their opioiduse, risking increased symptoms, in an attemptto avoid the burdens of bowel dysfunction.

Opioid-induced bowel dysfunction encom-passes delayed gastric emptying accompaniedby increased gastroesophageal reflux, as wellas constipation. Hard dry stool, gas distention,incomplete evacuation, and straining are com-mon sequelae. Severe dysfunction can lead tofrank pain from luminal stretch, nausea andvomiting, and dyspnea from limitation of dia-phragmatic excursion. These symptoms can beamplified when other conditions, such as ascitesor tumors, are present. If left untreated, consti-pation can progress to fecal impaction that inturn can cause urinary retention, delirium,and frank gastrointestinal (GI) obstruction.

About 40% of patients taking chronicopioids for nonmalignant pain develop boweldysfunction.1 The problem is even worse in

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104 Vol. 35 No. 1 January 2008Thomas

patients on chronic opioids who have advancedillness. This issue has been studied mostly incancer patients, and in this population, up to90% of patients on chronic opioid therapy de-velop bowel dysfunction.2 Although validatedquality-of-life tools exist for constipation, theyhave typically been applied to functionalconstipation, and there is a paucity of data onopioid-induced bowel dysfunction.

This review summarizes our current under-standing of normal GI physiology and howexogenous opioids cause bowel dysfunction. Italso summarizes current therapies for opioid-induced bowel dysfunction and their limita-tions. Despite best practices, the therapiesthemselves are often burdensome and some-times ineffective in providing relief. Finally, itreviews two investigational peripherally actingopioid antagonists, alvimopan and methylnal-trexone, that may provide relief from the suf-fering of opioid-induced bowel dysfunction.

Normal GI PhysiologyOverall, normal GI function includes secre-

tion, absorption, transport, and storage.3,4

Although the details of these processes varythroughout the length of the GI tract, thereare some common themes. In terms of intesti-nal motility, there are two basic forms ofcontractiondsegmental and peristaltic. Seg-mental contraction serves to mix luminalcontents in place and expose different surfacesto the mucosa to be acted upon by secretionor absorption. Peristalsis involves increasedmuscular tone proximally coordinated with

decreased muscular tone distally so that con-traction leads to forward movement of luminalcontents. In the small intestine, during fastingstates, ‘‘migrating motor complexes’’ occurabout every 90 minutes to sweep luminal con-tents from the duodenum to the ileum. About90 minutes is needed to traverse this distance.In the colon, ‘‘mass movements’’ occur on av-erage from one to three times per day; thesemovements propel luminal contents over largedistances. A local GI event also must be coordi-nated with other GI processes and systemicevents. For example, under ‘‘fight or flightconditions,’’ GI perfusion and motility are de-creased. After a meal, the gastrocolonic reflexleads to increased colonic motility. Finally,when the rectum is full, the rectosphinctericreflex leads to relaxation of the internal analsphincter.

These events are regulated via neurocrine,endocrine, paracrine, and autocrine mecha-nisms. The basic anatomy of the GI tract isshown in Fig. 1.5 Under the serosa, the smoothmuscle system of the GI tract consists of anouter longitudinal layer and an inner circularlayer, whereas the lumen is lined with the mu-cosal layer. In general, the smooth muscle cellsare in electrical contact via gap junctions, al-lowing synchronous contraction after stimula-tion by the neurotransmitter acetylcholine.

Nervous system control is mediated by bothintrinsic and extrinsic systems. The intrinsicenteric nervous system consists of the myenter-ic plexus that resides between the layers ofsmooth muscle and the submucosal plexusthat resides just beneath the mucosa. This en-teric ‘‘brain’’ consists of billions of neurons,

Fig. 1. Anatomy of the GI system (adapted from: Shetzline and Liddle 20025).

Vol. 35 No. 1 January 2008 105Opioid-Induced Constipation

including afferent neurons, efferent neurons,and interneurons utilizing neurotransmitters,such as acetylcholine, serotonin, vasoactive in-testinal peptide, and nitric oxide. Ninety-fivepercent of the body’s serotonin resides in theGI tract, and many of the subtypes of serotoninreceptors have been identified there. The5HT1p and 5HT4 serotonin receptor subtypesseem particularly important in mediatingcontractility.6

The extrinsic system consists of the auto-nomic nervous system. Parasympathetic inputis derived from the vagus and pelvic nerves,whereas sympathetic input arises from thethoracolumbar spine.

The interstitial cells of Cajal (ICC) commin-gle with the neurons and smooth muscle cellsof the GI tract (Fig. 2).7 The ICC are electri-cally coupled via gap junctions and generateoscillating ‘‘slow wave’’ activity that is conveyedto the smooth muscle via gap junctions also.These slow waves set the periodicity of smoothmuscle action potentials that occur at the peakof slow wave electrical activity. Finally, entero-chromaffin cells line the mucosa. They containserotonin that can be released by perturbationof their luminal surface by luminal contents.

Integration of input from all these systemsdetermines the patterns of secretion, absorp-tion, and motility that are established. Forexample, a meal triggers cholecystokinin re-lease that, through a series of secondary mes-sengers, ultimately leads to increased colonicmotility. Under stressful conditions, sympa-thetic input to the GI tract is increased, which

Fig. 2. ICC interactions (LM¼ longitudinal mus-cle; CM¼ circular muscle; ICMP¼myenteric plexusinterstitial cells; ICIM¼ intramuscular interstitialcells; ICSM¼ submucosal interstitial cells) (adaptedfrom: Cook and Brookes, 20027).

leads to decreased blood flow, decreased secre-tion, and decreased motility. When luminalcontents physically distort the mucosal entero-chromaffin cells, they release their serotoninstores, which then leads to a wave of communi-cation ultimately ending in smooth musclecontraction.

Disruption of this complex orchestration ofcommunication at the level of pacemaker cells,nerves, muscle, or transmitters can lead tobowel dysfunction. There are rare causes,such as congenital aganglionosis, myopathy,or anal dyssynergia, where pelvic floor musclescontract rather than relax with defecation.However, acquired causes of constipation aremuch more common. Endocrine/metaboliccauses include diabetes, hypothyroidism, andhypercalcemia. Psychologic conditions, suchas depression have been linked to an increasedincidence of constipation.8 Nerve function canbe perturbed by diseases, such as Parkinson’s,direct invasion by tumor, or paraneoplastic syn-dromes. Intrinsic or extrinsic luminal com-pression from masses can mechanically leadto constipation. Finally, medications, such ascalcium channel blockers, anticholinergicagents, antiserotonergic agents, and opioids,are prime mediators of constipation. Theremay be multiple etiologies in play, especiallyin advanced medical illnesses.

Opioid Interaction with the GI TractHow do opioids interact with this system?

Endogenous opioids include endorphins, en-kephalins, and dynorphins. They act selectivelyat opioid receptors composed of the mu, delta,and kappa types. Clinically used exogenousopioids, such as morphine, act predominantlyat the mu receptor. Thus, the mu receptor willbe the focus of this review.

Mu receptors are present in the central andperipheral nervous system, as well as the GItract. Localizations in the GI tract differ amongthe species studied and in the specific area of GItract. For example, using immunohistochemi-cal techniques, guinea pig mu receptors areidentified predominantly in the myentericplexus much more than the submucosal plexus.They also seemed to be intimately associatedwith but not on ICC. Moreover, mu receptorswere more abundant in the small intestine


than the large. In other animals, mu receptorsalso have been reported on the ICC and onsmooth muscle. In humans, mu receptorswere more consistently distributed betweenthe myenteric and submucosal plexi, and be-tween the small and large intestines. Therewas no evidence of mu receptors on the mucosalcells, the ICC, or the smooth muscle cells.9

The role of endogenous opioids in GI tractnormal function remains largely unknown. Itis believed that they play a role in normal phys-iologic control of motility based on experi-ments with systemic antagonists. Whennormal opioid-naı̈ve volunteers are treatedwith systemic opioid antagonists, such as nalox-one, measurable decreases in GI transit timeare observed.10

Exogenous mu agonists are known to affectthe GI tract in several ways. It is known thatthere are central nervous system-mediated GIeffects. If opioids are introduced intrathecally(either intraspinally or supraspinally), slowingof GI motility and decreased intestinal secre-tion are observed.11e13 However, it is also clearthat opioids can work peripherally at the levelof the GI tract itself. Opioids, such as lopera-mide, that do not cross the blood-brain barriercan induce GI slowing,14 isolated denervatedsegments of bowel show opioid-mediated slow-ing,15 and peripherally acting opioid antago-nists that do not cross the blood-brain barrier(alvimopan and methylnaltrexone) can pre-vent opioid-mediated slowing (as will be dis-cussed below). In response to exogenousopioids, decreased motility occurs at multiplelevels in the GI tract, including the stomach,small intestine, and large intestine.16 Thus,the predominant opioid effect appears to beat the local GI level.

Opioid receptors, including the mu receptor,are members of the seven transmembrane-span-ning G protein-coupled receptor superfamily.Mu receptors predominantly interact with Gi/Go proteins, although there is evidence of inter-action with Gs proteins also.17 The functionaloutcomes of this Gi/Go protein interaction are1) decreased levels of intracellular cAMP, 2) in-creased potassium conductance making neuronsless likely to fire, and 3) decreased calcium con-ductance leading to decreased neurotransmitterrelease. In the central nervous system, these mureceptor modulatory effects decrease neuro-transmission. Direct recording from enteric

neurons supports a similar inhibition of neuro-nal firing occurring in the GI tract also.18,19

Studies in various animals have demon-strated that under the influence of opioids,the outer longitudinal smooth muscle relaxes,but the inner circular smooth muscle has in-creased tone.16 It is believed that excitatoryneurons that innervate the longitudinalsmooth muscle are inhibited in their releaseof acetylcholine, leading to a decrease intone. However, it is believed that the circularsmooth muscle is tonically active and is underthe constant control of inhibitory neurons con-taining inhibitory neurotransmitters VIP andnitric oxide. Opioids inhibit this tonic inhibi-tion leading to increased tone in the circularmuscle layer. In vitro, peristalsis is blockedwhen trying to traverse an area under opioid ef-fect. The net effect is increased segmental con-traction but a decrease in productive forwardperistalsis. A byproduct of this disruption ofperistalsis, and resulting stasis of luminal con-tents is that there is increased passive absorp-tion of fluids leading to dryer and harder stools.

It is also clear that opioids play a direct rolein decreasing GI secretions.20 Opioids areknown to be able to inhibit secretions inducedby cholera toxin, vasoactive intestinal peptide(VIP), prostaglandin E1 (PGE1), and dibutyrylcyclic AMP (adenosine monophosphate). Thisopioid-mediated secretory inhibition can itselfbe inhibited by serotonin and adrenergic re-ceptor antagonists. This fact implicates seroto-nin and norepinephrine as downstreammediators of the opioid effect.

Overall, opioid inhibition of peristalsis andsecretion lead to the syndrome of opioid-induced bowel dysfunction.

Current Therapies for Opioid-InducedBowel Dysfunction

Despite the clinical importance of opioid-induced bowel dysfunction, there are few clin-ical trials on which to base current treatmentguidelines using approved medications. Thegoals of therapy typically include strategies tokeep stool volume maximized to trigger en-terochromaffin cell serotonin release via mu-cosal stretch. Also, by keeping stool softer, itis mechanically easier to move. Finally, effortsare undertaken to enhance peristalsis.


Fiber bulking agents are organic polymersthat retain water in stool. Studies support theefficacy of fiber in increasing the frequencyof bowel movements in chronic functionalconstipation.21,22 It is important that adequatewater be taken concomitantly with fiber. With-out sufficient water, fiber may worsen constipa-tion. Therefore, in patients with advancedillness who often have fluid deficits, fiber isnot recommended. Moreover, in the absenceof studies, it is widely believed on an empiricalbasis that fiber alone is insufficient to effec-tively treat opioid-induced bowel dysfunction.

Currently, many practitioners recommenda combination of a stool softener with a stimu-lant laxative for patients on chronic opioidtherapy.23 Stool softeners, such as docusate so-dium, are detergents that allow better waterpenetration into stool, making it softer andmore voluminous. Stimulant laxatives, such assenna and bisacodyl, induce peristalsis viamechanisms that are not well understood. Invitro, applying senna to intestinal mucosa leadsto immediate contraction. After optimal titra-tion of these agents, oral osmotics are com-monly added to enhance laxation by pullingalong water due to osmotic forces. Osmoticsinclude sugars, such as lactulose or sorbitol,magnesium salts, such as magnesium citrate,or inert substances, such as polyethylene gly-col. When unsuccessful, rescue oral and rectalinterventions are also often needed. Rectalinterventions include such agents as bisacodylsuppositories and phosphosoda enemas tosoften, lubricate, and mobilize hard, dry distalstool. Often synergism of multiple categoriesof agents is required for successful laxation.

There are also approved agents that theoret-ically could enhance peristalsis in opioid-induced bowel dysfunction, but again thereare no clinical trials to guide therapy. Neostig-mine, an acetylcholinesterase inhibitor that in-creases acetylcholine levels, has been used inOgilvie’s syndrome of acute colonic pseudo-obstruction.24 Acetylcholine, the final triggerfor smooth muscle contraction, could bypassopioid inhibitory modulatory effects, but alsoexposes patients to systemic effects of bradycar-dia and increased respiratory secretions. Givenserotonin’s key role in intestinal motility, selec-tive serotonin receptor agonists may playa role. Cisapride, a 5HT4 agonist, has effects in-creasing gastric, small intestinal, and colonic

motility. Unfortunately, it is no longer clini-cally available because of cardiac side effects.Metoclopramide, a dopamine antagonist thatis also a partial 5HT4 agonist, enhances gastricmotility, but is believed to have little coloniceffect. Tegaserod is a 5HT4 agonist that canenhance peristalsis and has been U.S. Foodand Drug Administration (FDA)-approved forchronic functional constipation and the con-stipating phase of irritable bowel syndrome.However, since this review was initially submit-ted, tegaserod has been voluntarily removedfrom the market. It is unclear whether theseserotonergic effects would come before or af-ter the opioid effects on neuronal pathways,but it warrants further study.

Several other agents have shown promise forchronic functional constipation, but againtheir role in opioid-induced bowel dysfunctionremains unknown. Misoprostol, a syntheticprostaglandin E1 analog, significantly de-creased colonic transit time and increasedstool weight in a one-week period in patientswith chronic functional constipation.25 How-ever, a longer open-label study revealed thatonly one-third of patients continued to havea response or could tolerate misoprostoldose-related side effects.26 Colchicine is an-other agent that has shown promise in a smallcontrolled trial of chronic functional constipa-tion. It decreased colonic transit times and in-creased the frequency of bowel movementsover four weeks.27 Finally, lubiprostone is a se-lective chloride channel (ClC-2) activator.28 Itis thought to work by increasing fluid secretionthat leads to an increase in the frequency ofspontaneous bowel movements. Based on twoPhase III trials, it has been FDA-approved forchronic functional constipation, although nostudy results have been published in peer-reviewed journals.

There are many hardships associated withthese current interventions for all patients,but especially for those with advanced medicalillness. Pill burden can be a troublesome issuefor many patients. Senna can be titrated up to12 pills a day for maximal effect. Together withother laxatives and other concomitant medica-tions, the problem of polypharmacy can besignificant.

Stimulant laxatives, such as senna and bisa-codyl are prodrugs that are activated in the GItract. Senna is metabolized to an active form


by bacterial action in the colon. Bisacodyl isactivated by small intestinal enzymes. Both caninduce painful abdominal cramping upon acti-vation. Chronic use of senna leads to melanosiscoli, a condition that has been debated as a pre-malignant state. Moreover, chronic senna usehas also been implicated in damage to the en-teric nervous system. Long-term studies in ratsfind no evidence of carcinogenicity or entericnervous damage, but the issues are not defini-tively settled in humans.29,30

Sugar-based osmotics work because humanscannot break down their disaccharide bonds;however, colonic bacteria can hydrolyze thisbond and metabolize the resultant monosac-charides, producing gas that can lead to un-comfortable bloating. Rectal interventions areoften considered uncomfortable, can affectpatient’s self-image, and challenge the bound-aries of caregivers who must assist a patient.

Loss of control also is often a significant is-sue. When laxation interventions are success-ful, the time of laxation can be unpredictableand present personal and social dilemmas.With these interventions, constipation can of-ten be overcome but sometimes tip the scaletoward frank diarrhea. All these interventionshave financial implications for the healthcare system also. Finally, despite these burdens,sometimes all the interventions are unsuccess-ful, and bowel dysfunction remains.

Opioid Antagonists for Opioid-InducedBowel Dysfunction

Ideally, one would like to specifically reverseperipherally mediated opioid-induced boweldysfunction without reversing centrally medi-ated analgesia. Systemic opioid antagonists,such as naloxone, have been studied in severalclinical trials.31e33 Oral naloxone has a lowbioavailability because of its rapid hepatic me-tabolism from the first pass effect. The hypoth-esis was that oral naloxone could achieve highenteric concentrations, reversing bowel dys-function without achieving systemic levels thatcould induce withdrawal and reverse centralanalgesia. Although the studies clearly showbowel dysfunction could be reversed, therewas often a clinically unacceptable percentageof unpredictable systemic opioid withdrawaland increased pain. Even when there was no

evidence of systemic withdrawal, there were ep-isodes of diarrhea that could be interpreted asa manifestation of GI withdrawal as opposed tosimple reversal of opioid-induced bowel dys-function. Liu and Wittbrodt noted that pa-tients on the highest doses of opioids seemedto be most sensitive to the opioid antagonistand at highest risk of withdrawal.33 This con-cept is supported by work that demonstratesthat persons with the highest degree of opioidphysical dependence or tolerance are mostsensitive to the effects of antagonists.34

To circumvent these systemic withdrawaleffects, peripherally acting opioid antagonistshave been developed and are undergoingclinical trials. Two are far along in the drug de-velopment processdalvimopan and methyl-naltrexone (Figs. 3 and 4). A search of theNational Library of Medicine reveals eight hu-man clinical trials of alvimopan’s effects, fourof which are related to opioid-induced boweldysfunction.35e38 There was one relativelylarge placebo-controlled trial (n¼ 168) assess-ing alvimopan efficacy in treating opioid-induced bowel dysfunction in patients onchronic opioids.36 A similar search reveals 12human clinical trials of methylnaltrexone’s ef-fects, eight of which are related to opioid-induced bowel dysfunction.39e46 Two of theseassessed the efficacy of methylnaltrexone foropioid-induced bowel dysfunction in patientson chronic opioids. One was a single-blindprospective trial of oral methylnaltrexone(n¼ 12), and the other was a placebo-controlled, double-blind study of intravenousmethylnaltrexone (n¼ 11). Large Phase IIIclinical trials are under way or have been con-ducted for both agents, but results to date havenot been published in peer-reviewed journals.

Alvimopan is a zwitterionic molecule (con-taining both a positive and a negative charge;Fig. 3), with a molecular weight of 460.1 Da.

Fig. 3. Chemical structure of alvimopan.


It is a mu receptor-selective antagonist witha Ki of 0.77 nM at the mu receptor, 4.4 nM atthe delta receptor, and 40 nM at the kappa re-ceptor.47 For comparison, naloxone has a Ki atthe mu receptor of 3.7 nM. Opioid-dependentmice were used to assess alvimopan’s activity atperipheral and central opioid receptors. Activ-ity at peripheral GI opioid receptors wasassessed by inducing withdrawal diarrhea.Central activity was assessed by antagonizinganalgesia. When alvimopan was given intrave-nously to these mice, it was 200 times morepotent at the peripheral GI receptors than atcentral receptors. This peripheral selectivity ispresumably because of its zwitterionic nature,reducing its ability to cross the blood-brainbarrier. In dogs, alvimopan is only w0.03%bioavailable because of poor systemic absorp-tion; it has a serum half-life of about 10 min-utes.37 Thus, poor oral bioavailability togetherwith poor blood-brain barrier permeabilityappear to synergize to make oral alvimopanless likely to reach sufficient systemic levels tohave central nervous system effects. This pe-ripheral restriction also has been confirmedin humans when alvimopan is given orally.36,38

Liu et al. studied patients after third molarextraction. They were given intravenous mor-phine (0.15 mg/kg) postoperatively and eitherplacebo or alvimopan 4 mg orally. Alvimopanhad no effect on the centrally mediated opioideffects of analgesia or pupil constriction, sup-porting its peripheral restriction. There areno human studies of parenteral alvimopaneffects reported.

Alvimopan has been shown to counteropioid-induced delays in GI transit. However,further clinical studies of alvimopan havebeen suspended due to an apparent increasein cardiovascular events for subjects who re-ceived alvimopan versus placebo.35,38 The lac-tulose hydrogen breath test uses the fact thatlactulose must be metabolized by colonic bac-teria to release hydrogen as a measure of thetime it takes to traverse the GI tract from themouth to the cecum. Intravenous morphine(0.05 mg/kg) was shown to increase this transittime. Compared to placebo, alvimopan 4 mgorally could reverse this GI slowing. Gonenneet al. gave volunteers either codeine 30 mg orplacebo orally four times a day, plus eitheralvimopan 12 mg or placebo orally twicea day. Motility was measured by following

labeled egg meal and charcoal by scintigraphy.They demonstrated that codeine delayedgastric emptying, as well as small and largeintestine transit. Alvimopan reversed opioid-induced slowing of the small and large intes-tines but failed to reverse the slowing of gastricemptying. Consistent with previous studies ofsystemic opioid antagonists, alvimopan givenin the absence of opioids decreased GI transit,again implying a role for endogenous opioidsin the tonic control of GI motility.

Alvimopan’s efficacy for opioid-inducedbowel dysfunction was assessed in a double-blind, randomized, placebo-controlled trial of168 patients on chronic opioids, either for opi-oid dependence or for chronic pain.36 Patientswere on opioids for at least one month ata level of 10 mg oral morphine equivalentper day or higher. They had bowel dysfunctionas evidenced by ‘‘preferably <3 bowel move-ments (BMs) per week,’’ associated with atleast one of the following symptoms: lumpyor hard stools, straining, sensation of anorectalobstruction, or sensation of incomplete evacu-ation. The 49-day trial consisted of 14 days ofbaseline assessment, 21 days of treatment,and 14 days of post-treatment assessment. Pa-tients were randomized to one of three arms:placebo, alvimopan 0.5 mg orally per day, oralvimopan 1 mg orally per day. Patients wereallowed to continue their baseline bowel regi-men but were not allowed to use rescue laxa-tives, such as enemas. Overall, patients wereon a median oral morphine equivalent dailydose of approximately 100 mg, with a rangefrom 10 to 1,500 mg per day. The primary out-come was the proportion of patients with atleast one BM within eight hours of studydrug administration on each day during the21-day treatment period, averaged across allpatients. During the baseline assessment,mean frequency of BMs was about four perweek in each arm, in contrast to the inclusioncriteria of <3 BMs per week. Thus, patients didnot appear to have been as constipated as thestudy intended.

Both alvimopan doses showed a statisticallysignificant improvement in the primary out-come. The average proportion of patients hav-ing a BM within eight hours of dosing over thetreatment period improved from 29% for pla-cebo to 43% for alvimopan 0.5 mg to 54%for alvimopan 1 mg. As a secondary endpoint,


the response rate and response time for thefirst dose of study drug were captured. In theplacebo group, 27% responded within eighthours, compared to 57% for alvimopan0.5 mg and 74% for alvimopan 1 mg. The me-dian time to laxation after the first dose was21 hours, 7 hours, and 3 hours for placebo, al-vimopan 0.5 mg, and alvimopan 1 mg, respec-tively. Only the higher alvimopan dose wasstatistically significantly faster than placebo.The frequency of BMs per week was also cap-tured. The higher alvimopan dose showeda statistically significant increase in BM fre-quency throughout the treatment periodcompared to placebo, but there was no differ-ence between the lower alvimopan dose andplacebo. Of note, there was no decrease inconcomitant laxative therapy during the treat-ment phase.

In terms of tolerability, this study observedno reports of increased pain, consistent withthe expectation that the drug did not crossthe blood-brain barrier to a clinically signifi-cant degree. There were no significant adverseevents deemed related to alvimopan. However,there appeared to be a dose-related increase inthe most commonly reported adverse events:abdominal cramping, flatus, nausea, vomiting,and diarrhea. In the alvimopan 1 mg group,11% (six patients) dropped out of the studybecause of these adverse events, compared to3% with the lower alvimopan dose, and 2%in the placebo group. Some abdominal cramp-ing and flatus can be considered part of thephysiological process of having a BM, espe-cially when constipation is present. However,more severe cramping, nausea, vomiting, anddiarrhea may be a sign of local GI opioid with-drawal, seen previously with naloxone studies.

Methylnaltrexone is a positively chargedmolecule (Fig. 4), with a molecular weight of436.36 Da. It is also a mu receptor-selective an-tagonist with a Ki of 70 nM at the mu receptor.It has a Ki of 575 nM at the kappa receptor anddoes not appear to bind the delta receptor. Itsserum half-life is about 2.5e3 hours.39 Its pe-ripheral selectivity was first demonstrated in an-imals.48 In dogs, intravenous methylnaltrexonecould inhibit morphine-induced duodenalspike potentials at concentrations that did notlead to signs of centrally mediated systemic with-drawal in opioid-dependent animals. In humans,methylnaltrexone 0.3 mg/kg intravenously did

not antagonize morphine’s (0.125 mg/kg) cen-tral depression of hypoxic ventilatory drive.49

Methylnaltrexone (intravenously, subcuta-neously, and orally) has been shown to reversemorphine-induced oral-cecal transit delay, asmeasured in the lactulose hydrogen breathtest.40,42,45,46 Unlike alvimopan, Murphy et al.demonstrated that intravenous methylnaltrex-one could also inhibit opioid-induced delay ingastric emptying.44 Similar to naloxone and al-vimopan, intravenous methylnaltrexone alonein opioid-naı̈ve volunteers also decreased GItransit time.39

Two oral formulations have been used inmethylnaltrexone studies.41,42 One was un-coated, and the other was enteric-coated toprevent gastric absorption. Using uncoatedmethylnaltrexone, 19.2 mg/kg could com-pletely reverse the delayed transit caused by in-travenous morphine 0.05 mg/kg. The enteric-coated form delivered at 6.2 mg/kg not onlyreversed the opioid-induced delay but de-creased transit time below baseline. Presum-ably, the enteric-coated form reduced gastricabsorption and delivered a higher methylnal-trexone concentration to the GI lumen. The‘‘flip side’’ of this phenomenon was that theenteric-coated form also reached significantlylower serum levels. The uncoated methylnal-trexone, in fact, reached sufficient serumlevels to reduce other morphine side effects,such as being ‘‘nauseous’’ and having ‘‘skinitch’’ believed to be mediated at other periph-eral sites outside the GI tract.50 Whether theoral delivery of such levels is clinically practicaland affordable remains to be seen.

Methylnaltrexone’s ability to reverse opioid-induced bowel dysfunction was assessed in twosmall published trialsdone oral and one intra-venous. The oral study was single blind, carriedout over two days.41 Twelve chronic metha-done users who had opioid-induced bowel

Fig. 4. Chemical structure of methylnaltrexone.


dysfunction as evidenced by #2 BMs per weekwere enrolled. The mean methadone dose was73.3 mg/day. On the first day, groups of fourpatients received placebo, and on the secondday, the groups received one of three ascend-ing doses of oral methylnaltrexone (0.3, 1, or3 mg/kg). Laxation and time to laxationwere captured. None of the twelve had a laxa-tion response to placebo. At the 0.3 mg/kgdose, three of four patients had laxation ata mean time of 18 hours after dosing. At the1 and 3 mg/kg dose, all subjects had laxationat median times of 12.3 and 5.2 hours afterdosing, respectively. The authors noted,‘‘most patients reported very mild abdominalcramping. described as similar to defeca-tion.’’ There were no signs of systemic with-drawal, and there were no adverse events.Given the small sample size, definitive conclu-sions about tolerability and safety cannot bemade.

Intravenous methylnaltrexone was studied ina double-blind, randomized, placebo-controlledtrial of 22 chronic methadone users.43 Theyhad been on methadone for $1 month on anaverage dose of about 62 mg/day. All subjectshad opioid-induced bowel dysfunction as evi-denced by #1 BM in the previous three daysor #2 BMs in the previous week. For twodays before, and for the duration of the study,there was no laxative use. They were random-ized to receive, on two separate occasions,either placebo or escalating doses of methyl-naltrexone intravenously. A series of up tofour infusions separated by one minute weregiven until the patients had either a BM oran adverse event. The methylnaltrexone infu-sions were calculated to sequentially deliver0.015, 0.05, 0.1, and 0.2 mg/kg. No patientswho received the series of placebo infusionshad laxation in either of the two sessions.Ten of 11 subjects randomized to methylnal-trexone had immediate laxation in the first ses-sion, and 11 of 11 had immediate laxation inthe second session. Immediate laxation was de-fined as a BM during the infusion or withinone minute of its cessation. The mean dose re-ceived before laxation was about 0.1 mg/kg.This dose is in contrast to an intravenousdose of 0.45 mg/kg used to reverse transitslowing in opioid-naı̈ve subjects given an acutedose of morphine 0.05 mg/kg. This differenceunderscores the previously discussed apparent

antagonist sensitivity of chronic opioid users.The authors reported that subjects had ‘‘mildto moderate abdominal cramping.similar toa defecation sensation without discomfort.’’One patient did experience diarrhea. Therewere no signs of systemic withdrawal. Againthis study was small, and definitive safety con-clusions cannot be drawn. Of note, in the pilotstudy that preceded this trial, one chronicmethadone user who received a larger dose,0.45 mg/kg, intravenous methylnaltrexone ex-perienced severe cramping and had to be with-drawn from the study.51

Overall, clinical studies to date are encour-aging that peripherally acting opioid antago-nists may be efficacious and well tolerated.Oral forms of alvimopan and methylnaltrex-one may provide a noninvasive rescue frombowel dysfunction with a relatively predictablelaxation response in hours once dosing is opti-mized. Methylnaltrexone also is available ina parenteral form that may be useful whenthe oral route is not available or when a fasterrescue laxation response is desired. Publishedresults from large Phase III trials are eagerlyawaited.

In addition to basic efficacy and safety issuesto be addressed by these larger definitive trials,several other issues remain. What is the opti-mal ratio of peripheral antagonist to opioid ag-onist, and what is the role of tolerance in thisratio? Who is at risk of local GI withdrawalsymptoms and how is that best mitigated?Can these peripheral opioid antagonists sparethe use of other laxatives? If some laxatives arestill required, what class of agent is needed foroptimal synergy? What will be the efficacy ofthese agents in cases where bowel dysfunctionmay have multiple etiologies? For example,patients with advanced illness, such as cancer,who are on opioids may also be on otherconstipating medications, have electrolyte orhormonal abnormalities, or have autonomicneuropathy that may complicate therapy withthese opioid antagonists. Finally, what is therole of these peripheral antagonists in prevent-ing opioid-induced bowel dysfunction in thefirst place?

In summary, opioid-induced bowel dysfunc-tion remains a clinically important problemthat is the source of much suffering. As thephysiology and pathophysiology of the GI tractis elucidated, new treatment approaches are


anticipated. Peripheral-acting opioid antago-nists hold much promise as a new weapon inour armamentarium to treat opioid-inducedbowel dysfunction. Especially in patients withadvanced illness, these new agents may providerelief from current therapeutic burdens, re-turn some control to their lives, and restoresome quality of life.

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Opioid-Induced Bowel Dysfunction