Aalborg Universitet Opioid-Induced Constipation and Bowel ... · Introduction Pain, when not effectively treated and relieved, has det-rimental effects on all aspects of a patient’s

Aalborg Universitet

Opioid-Induced Constipation and Bowel Dysfunction

A Clinical Guideline

Muumlller-Lissner Stefan Bassotti Gabrio Coffin Benoit Drewes Asbjoslashrn Mohr BreivikHarald Eisenberg Elon Emmanuel Anton Laroche Franccediloise Meissner Winfried MorlionBartPublished inPain Medicine

DOI (link to publication from Publisher)101093pmpnw255

Creative Commons LicenseCC BY-NC 40

Publication date2017

Document VersionPublishers PDF also known as Version of record

Link to publication from Aalborg University

Citation for published version (APA)Muumlller-Lissner S Bassotti G Coffin B Drewes A M Breivik H Eisenberg E Emmanuel A Laroche FMeissner W amp Morlion B (2017) Opioid-Induced Constipation and Bowel Dysfunction A Clinical GuidelinePain Medicine 18(10) 1837-1863 httpsdoiorg101093pmpnw255

General rightsCopyright and moral rights for the publications made accessible in the public portal are retained by the authors andor other copyright ownersand it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights

Users may download and print one copy of any publication from the public portal for the purpose of private study or research You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the URL identifying the publication in the public portal

Take down policyIf you believe that this document breaches copyright please contact us at vbnaubaaudk providing details and we will remove access tothe work immediately and investigate your claim

GENERAL SECTION

Review Article

Opioid-Induced Constipation and BowelDysfunction A Clinical Guideline

Stefan Muller-Lissner MD Gabrio Bassotti MDdagger

Benoit Coffin MDDagger Asbjoslashrn Mohr Drewes MDsect

Harald Breivik MDpara Elon Eisenberg MDk

Anton Emmanuel MDkj Francoise Laroche MDWinfried Meissner MDdaggerdagger and Bart Morlion MDDaggerDagger

Department of Internal Medicine Park-Klinik

Weissensee Berlin Germanydagger

Gastroenterology and

Hepatology Section Department of Medicine

University of Perugia School of Medicine Piazza

Universita 1 Perugia ItalyDagger

AP-HP Hopital Louis

Mourier University Denis Diderot-Paris 7 INSERM

U987 Paris France sectDepartment of Gastroenterology

and Hepatology Aalborg University Hospital Aalborg

Denmark paraDepartment of Pain Management and

Research University of Oslo Rikshospitalet Oslo

Norway kInstitute of Pain Medicine Rambam Health

Care Campus The Technion Israel Institute of

Technology Haifa Israel kjGI Physiology Unit

University College Hospital Queen Square London

UK Saint-Antoine University Hospital Paris Francedaggerdagger

Jena University Hospital Jena GermanyDaggerDagger

Leuven Center for Algology and Pain Management

University of Leuven KU Leuven Leuven Belgium

Funding sources Funded by an unrestricted educa-

tional grant from Mundipharma International

Disclosures and conflicts of interest Stefan Muller-

Lissner consultancy for Mundipharma International

Develco and Astra Zeneca Gabrio Bassotti consult-

ing fees from Mundipharma International and lecturing

fee from Shire Pharmaceutical for educational pur-

poses Benoit Coffin no conflict of interest Asbjoslashrn

Mohr Drewes no conflict of interest Harald Brevik no

conflict of interest Elon Eisenberg grant from

Mundipharma International to study opioid-induced

hyperalgesia Anton Emmanuel advisory board for

NAPP Shire and Takeda Francoise Laroche consult-

ancy for Mylan Grunenthal and Mundipharma

International Winfried Meissner advisory boards for

Menarini Grunenthal BioQPharma Medicines

Company and Mundipharma International No com-

peting interests

Correspondence to Stefan Muller-Lissner MD

Eisenacherstrasse 103D 10781 Berlin Germany Tel

thorn49 30 21997504 Mobile thorn49 151 12629359 Fax

thorn49 96 283605 E-mail stefanmueller-Lissnerde

Abstract

Objective To formulate timely evidence-basedguidelines for the management of opioid-inducedbowel dysfunction

Setting Constipation is a major untoward effect ofopioids Increasing prescription of opioids has cor-related to increased incidence of opioid-inducedconstipation However the inhibitory effects of opi-oids are not confined to the colon but also affecthigher segments of the gastrointestinal tract lead-ing to the coining of the term ldquoopioid-inducedbowel dysfunctionrdquo

Methods A literature search was conducted usingMedline EMBASE and EMBASE Classic and theCochrane Central Register of Controlled TrialsPredefined search terms and inclusionexclusioncriteria were used to identify and categorize rele-vant papers A series of statements were formulatedand justified by a comment then labeled with thedegree of agreement and their level of evidence asjudged by the Strength of RecommendationTaxonomy (SORT) system

Results From a list of 10832 potentially relevantstudies 33 citations were identified for reviewScreening the reference lists of the pertinent papersidentified additional publications Current defin-itions prevalence and mechanism of opioid-induced bowel dysfunction were reviewed and atreatment algorithm and statements regarding pa-tient management were developed to provide

VC 2016 American Academy of Pain Medicine

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (httpcreativecommonsorg

licensesby-nc40) which permits non-commercial re-use distribution and reproduction in any medium provided the original work is properly cited

For commercial re-use please contact journalspermissionsoupcom 1837

Pain Medicine 2017 18 1837ndash1863doi 101093pmpnw255

Downloaded from httpsacademicoupcompainmedicinearticle-abstract181018372649200by gueston 01 February 2018

guidance on clinical best practice in the manage-ment of patients with opioid-induced constipationand opioid-induced bowel dysfunction

Conclusions In recent years more insight hasbeen gained in the pathophysiology of this ldquoentityrdquonew treatment approaches have been developedbut guidelines on clinical best practice are still lack-ing Current knowledge is insufficient regardingmanagement of the opioid side effects on the uppergastrointestinal tract but recommendations can bederived from what we know at present

Key Words Opioids Constipation OpioidAntagonists PAMORAs Laxatives

Introduction

Pain when not effectively treated and relieved has det-rimental effects on all aspects of a patientrsquos quality oflife (QoL) [1] Opioids represent the cornerstone of paintreatment being the most commonly prescribed medi-cation to treat severe pain in the Western world [2]Opioids are increasingly used for the treatment also ofnoncancer pain [3] However opioids are associatedwith side effects which include sedation physical de-pendence respiratory depression and gastrointestinal(GI)-related side effects [4] These side effects can dir-ectly reduce patient QoL and increase medical serviceuse but may also be dose limiting thus affecting paincontrol [56] While tolerance develops to most side ef-fects GI side effects remain an ongoing problem for themajority of patients [5]

GI-related side effects are mediated through the bindingof opioid agonists to l-receptors located in the entericnervous system which causes increased nonpropulsivecontractions and inhibition of water and electrolyte ex-cretion leading to delayed GI transit and hard infre-quent stools [478] A less common side effect ofopioids is narcotic bowel syndrome (NBS) characterizedby a paradoxical increase in abdominal pain associatedwith continuous or increasing doses of opioids [9]

GI-related side effects which include constipation nau-sea vomiting dry mouth gastro-oesophageal refluxabdominal cramping spasms and bloating are collect-ively known as opioid-induced bowel dysfunction (OIBD)[410] Opioid-induced constipation (OIC) is the mostfrequently reported and persistent side effect in patientsreceiving opioids for analgesia [11] This review aims toevaluate the current understanding of OIBD and providetimely evidence-based recommendations for the man-agement of patients affected by this condition

Methods

A search of the medical literature was conducted usingMedline (1946ndashSeptember 2014) EMBASE and

EMBASE Classic (1947ndashSeptember 2014) and TheCochrane Central Register of Controlled Trials

Potentially relevant studies were identified using theterms listed in the Appendix Using further search terms(also listed in the Appendix) the identified studies werecategorized as relating to prevalence epidemiologymechanisms nonpharmacological treatment pharmaco-logical treatment and treatment with opioid antagonists

In total the search yielded 10832 unique citations(Figure 1) For inclusion all studies were required to beperformed in a population of adults who were receivingopioids and who had a confirmed diagnosis of OIBDbased on clinical symptoms physicianrsquos opinion ordiagnostic criteria specified by study investigatorsStudies identified within the treatment categories werealso required to be randomized controlled trials (RCTs)comparing pharmacological or nonpharmacologicaltherapies with a control measure There was no min-imum duration of therapy but quantitative assessmentof response to therapy was required Results had to besupplemented by negative investigations (eg colonos-copy) where deemed necessary by the trial Only publi-cations in English were included in the analysis Usingthe above inclusion and exclusion criteria the identifiedcitations were screened independently by two investiga-tors for relevance by title and then abstract which re-sulted in 124 and 52 citations respectively Fullpublications of the 52 citations were assessed and fol-lowing discussion to resolve any disagreement a finallist of 33 citations was generated [12ndash44] Screening thereference lists of the pertinent papers identified add-itional publications

Statements were then formulated and justified by acomment The statements were labeled with the degreeof agreement (usually unanimous) and their level of evi-dence by the strength of recommendation taxonomy(SORT) system (level 1frac14 high level 2frac14moderate level3frac14 low) [45] This corresponds to the classification bythe GRADE system where the levels of evidence ldquolowrdquoand ldquovery lowrdquo are pooled [46] The strength of recom-mendation is given as ldquostrongrdquo or ldquoweakrdquo when applic-able Independent electronic voting was carried out aftera joint meeting where all authors had the possibility todiscuss the different sections and comment on eachstatement The table showing the results can be foundin the Appendix

Definition Symptoms and Assessment of OIC andOIBD

The Definition of OICOIBD Is Based on a ClinicalEvaluation Relating to a Change in Bowel HabitsDuring Opioid Therapy

Comment Previously the diagnosis was arbitrarilybased on changes in bowel function temporally associ-ated with intake of opioids A recent working group

Muller-Lissner et al

suggested that OIC was defined as follows ldquoA changewhen initiating opioid therapy from baseline bowel habits(over 7 days) that is characterized by any of the follow-ing reduced bowel movement frequency developmentor worsening of straining to pass bowel movements asense of incomplete rectal evacuation or harder stoolconsistencyrdquo [47] A somewhat comparable definitionwas recently suggested based on a systematic literaturereview [48] These definitions represent the first attemptsto ensure a uniform diagnosis and this definition is rec-ommended for future studies to ensure a uniformterminology

The Symptoms of OIC Are Related to the Colon

Whereas OIBD Manifests with Symptoms

Throughout the GI Tract

Comment Opioid receptors are present throughout theGI tract and therefore symptoms should not be re-stricted to the colon [49] OIBD is a distressing conditionthat manifests through a variety of different symptomsincluding vomiting dry mouth abdominal pain gastro-esophageal reflux and constipation [4] Descriptivestudies have demonstrated that patients undergoingopioid treatment also had prevalent complaints relatedto the upper gut [172030] However most clinicalstudies looking into adverse effects of opioids and opi-oid antagonists have focused on OIC and especially onthe number of complete bowel movements that can bequantified It should also be stressed that straining atstools can cause upper GI symptoms such as refluxand it is therefore questionable as to whether OIC andOIBD can be distinguished in clinical settings

OIBD symptoms are potentially difficult to localize anddistinguish from each other due to the complex organ-ization of the visceral sensory system visceral afferentsshow diffuse termination over many segments of thespinal cord [50ndash52] It is therefore plausible that colonicdistension due to OIC may also be felt in the upperabdomen Furthermore mechanisms such as viscero-visceral hyperalgesia may play a role for symptommanifestations as afferents from somatic structures anddifferent visceral organs often terminate on the sameneurons in the spinal cord [53ndash55] As a consequenceit has been shown that the acidification of the esopha-gus may result in widespread changes in pain percep-tion from remote organs such as the rectum [56ndash58]Although not investigated in detail it seems plausiblethat opioid treatment also results in widespread symp-toms in most patients

Importantly while the effect on pain may decrease dur-ing continuing opioid treatment OIC tends to remain aclinical problem and is not subject to tolerance [59]

Subjective Reports of OIC Are Based on Validated

Questionnaires Whereas There Is No Consensus

About Assessment of OIBD

Comment In many studies symptom assessmentswere based on self-made questionnairesQuestionnaires developed and validated to assess ldquonor-malrdquo constipation such as the Bristol Stool Form ScalePatient Assessment of Constipation Scale and theKnowles-Eccersley-Scott symptom scoring systemhave also been used although the sensitivity of these

Figure 1 Flow diagram showing review of literature to identify clinical research papers relating to OIBD

Clinical Guidelines for OIC and OIBD

questionnaires when used by opioid users has not beenassessed [374760] Alongside the introduction of slow-release oxycodonenaloxone combinations designed toreduce OIC a new and specific questionnaire was de-veloped This is termed the Bowel Function Index (BFI)and is a clinician-administered questionnaire to evaluateand assess OIC The BFI has been validated against thePatient Assessment of Constipation Scale bowel move-ments and laxative use with excellent correlation beingfound [61]

For OIBD there is no valid assessment tool specificallydesigned to measure the burden of these symptomsInstruments such as the Gastrointestinal SymptomRating Scale are well validated for general GI symptomsand are available in many languages [62] Howeversensitivity to opioid-induced adverse events will requirefurther investigation The questionnaire will also requiresupplementary questions to increase its specificity forOIBD Recently the use of several outcome variablesbased on objective measures (eg bowel movements)patient-reported assessment with questionnaires and aglobal measure of burden such as life quality were sug-gested [48] Future studies are however needed to ex-plore the reliability and validity of these tools

Objective Assessment of OIBD Has Focused on

Motility but There Are Only a Few Human Studies

on Opioid Effects on Secretion and Sphincter

Function

Comment Self-reported number of bowel movementsand time to bowel movement may be used as objectivemeasures of OIC The feces can be quantified withsemi-objective questionnaires such as the Bristol StoolForm scale [60] When it comes to more physiologicalmeasurements most studies have focused on motilitydisturbances where transit time was measured in differ-ent ways [6364]

No methods are able to estimate the total flux of waterin the human intestine Fecal collection and measure-ment of water content is possible but difficult to use inclinical practice Secretion of water from the gut mucosacan be directly assessed from biopsies in an Ussingchamber [65] It is also possible to quantify the amountof feces within the colon based on magnetic resonancescanning but no such studies have yet been performedto address OIBD [6667]

Sphincter tone has been shown to be increased follow-ing opioid treatment however there is only one studythat has demonstrated a pressure increase of thehuman internal sphincter during opioid treatment[6869] Methods such as the Functional LumenImaging Probe and high-resolution manometry may in-crease our knowledge about anal sphincter function inthe near future [7071]

Prevalence

Data on Prevalence of OIC Differs Widely Based onthe Definitions Used and Origin of the Studies butNot on Gender

Comment The prevalence of constipation was reportedin 22ndash81 of patients [1420] Prevalence rates relate tothe instrument usedmdashin a study of 520 individuals theprevalence was 59 according to the BFI 67 usingthe KnowlesndashEccersleyndashScott symptom score and 86according to the clinicianrsquos opinion [37] Prevalence ofOIC is not related to gender (odds ratios frac14 1125malefemale) [30]

The Type of Pure Opioid Drugs Does Not Influencethe Prevalence of OIC Symptoms

Comment One placebo-controlled study of opioidsshowed a 14 rate of constipation with placebo vs 39ndash48 for various forms of oxycodone and oxymorphone[72] A review of different opioids showed no differencein rates of OIC between morphine hydrocodone andhydromorphone [73] A recent approach to reduce OICis through dual action drugs One of these tapentadolis an opioid with classic l-agonistic properties that alsohas simultaneous action as a noradrenaline reuptake in-hibitor [74] Hence for an equianalgesic dose less l-agonism is required in opioid-naıve patients [75ndash77]However experienced pain specialists have seen with-drawal when patients have been switched from long-term treatment with potent opioids to an ldquoequipotentrdquodose of tapentadol without first tapering the opioid

Dose and Frequency of Opioids InfluencesLikelihood of OIC Symptoms

Comment In one study daily use of opioids led to re-ports of constipation in 81 of patients whereas only46 of patients using opioids two to three times perweek reported constipation [20] The study documentedthat daily opioid users tended to take more than onetype of opioid

Transdermal Preparations of Fentanyl andBuprenorphine May Be Associated with LowerIncidence of OIC than Oral Opioids

Comment The rates of constipation reported for trans-dermal opioids are numerically lower than for oral opioidsIn a nonrandomized retrospective study the rates ofconstipation were 37 for transdermal fentanyl 61for oxycodone controlled-release (CR) and 51 for mor-phine CR [78] Similar findings reproducing these ex-tremely low incidences of OIC were seen with fentanylpatch (5) vs morphine (6) [79] A systematic review of14 studies on buprenorphine showed lower rates of

constipation for buprenorphine than for morphine andsimilar rates to those reported for fentanyl Howeverthere were no direct comparisons of the two transdermalopioids [80] Patch administration of buprenorphine doesindeed cause constipation A buprenorphine patch (me-dian dose 10 ughour) caused constipation in 24 of100 osteoarthritis patients compared with only 5 in theplacebo-patch group [81] The opioid when releasedfrom the patch will still reach the intestinal circulationand enteric nervous system and therefore may exert itsinhibitory effect on motility However the more uniformblood opioid concentration provided by the patch par-ticularly in regards to reduced peaks in concentrationmay be advantageous It is also important to rememberthat caution must be taken when interpreting theprementioned data as there are no high-quality compara-tive trials between oral and transdermal opioids

Duration of Opioid Therapy Influences the Impact ofOIC Symptoms

Comment A systematic review of 11 studies including2877 patients with nonmalignant pain identified thatopioid treatment for more than six weeks significantlyimproved QoL and functional outcomes [82] Howeverpatients who had been taking opioid analgesia for morethan six months and suffering OIC had a higher impacton their QoL as well as impairment of in-work product-ivity and activities of daily living (in all comparisons) andgreater work time was missed than for patients withoutOIBD [83] Though this statement is based on an indir-ect comparison we do know that opioid treatment formore than six weeks can improve QoL and that there isa difference in impact on QoL between patients withOIC and without OIC As such there needs to be ajudgment made that balances the benefits of chronicopioid usage against the risks of intestinal symptoms

Mechanisms of OIBD

Opioid Receptors Are Spread Throughout the GITract from the Mid-Esophagus to Rectum and AreInvolved in a Variety of Cellular Functions

Comment d- j- and l-opioid receptors have beenidentified in the GI tract [84] These receptors are pre-dominantly found in the enteric nervous system but theirrelative distribution varies within regions and histologicallayers of the gut and most importantly between species[8586] In rats l-receptors are widely distributed in themyenteric plexus where they control motility as well asin the submucosal plexus where they mainly regulate ionand water transport [85ndash88] The endogenous opioid lig-ands (eg enkephalins endorphins and dynorphins)have correspondingly been localized in the same regions[89] In humans the distribution of the different opioid re-ceptors and subclasses is less thoroughly investigatedbut m-receptors in the enteric nervous system arethought to be of utmost importance [86]

Endogenous ligands play a role in normal regulation ofGI function but opioid receptors are also activated byexogenous opioids [869091] Opioid-induced intracel-lular signaling is complex but leads to decreased neur-onal excitability and less neurotransmitter releaseresulting overall in an inhibitory effect on the cells Themain effect is thought to be decreased formation of cyc-lic adenosine monophosphate a molecule involved inthe activation of several target molecules that regulatecellular functions [92] The effect opioids have on GImotility and secretion is further complicated by opioidreceptor agonistsrsquo ability to influence both excitatoryand inhibitory activity as well as activating the interstitialcell of the Cajalndashmuscle network [84]

Opioid Agonists Administration Results in Slowingof Normal GI Motility Segmentation IncreasedTone and Uncoordinated Motility Reflected in forExample Increased Transit Times

Comment Gut motility is mainly controlled by the my-enteric plexus This is dependent on neurotransmitterswhere acetylcholine activates the motor neurons in thelongitudinal smooth muscles whereas vasoactive intes-tinal peptide and nitric oxide control the inhibition of in-hibitory motor neurons in the circular smooth muscles[4993] As opioid administration inhibits the release ofthe neurotransmitters it directly results in an increase intone and a decrease in the normal propulsive activity l-opioid receptors are likely of most importance as the ef-fect of morphine on GI motility is absent in l-receptorknockout mice [94] Central effects of opioids on motilitymay play a role via sympathetic activation but are likelyto be of minor importance [95]

The results of the animal experiments were confirmedin vitro on isolated human gut strips [96] Furthermorein vivo human studies have confirmed that opioid ad-ministration leads to dysmotility of the esophagus andgallbladder and increase of tone in the stomach [9397ndash99] as well as a delay in gastric emptying oral-coecaltransit and colonic transit time [6469100]

Although confirmation is required in other species a re-cent study in mice suggests that the effect of opioidson the gut may vary between opioids [101] Hence opi-oids such as tapentadol which have effects on the nor-adrenergic system may preserve the analgesic effectswith fewer adverse effects on the gut [102]

Opioids Result in Increased Absorption andDecreased Secretion of Fluids in the Gut Leadingto Dry Feces and Less Propulsive Motility

Comment Opioids inhibit acetylcholine release whichcan lead to a decrease in saliva production resulting inthe symptom of dry mouth In the gut the submucosalplexus controls local secretory and absorptive activity

[59103] Acetylcholine along with serotonin andvasoactive intestinal peptide is released from neuronsactivating intracellular mechanisms in mucosa cells andsubsequently epithelial cell chloride channels As chlor-ide moves from the enterocyte cytoplasm into the gutlumen water follows via an osmotic gradient[91101104]

Opioids bind to the secretomotor neurons in the sub-mucosa and suppress neurotransmitter release result-ing in a decrease in chloride and water secretion [91] Inthis way gut secretion and absorption is affected to-gether with gastric and pancreatico-biliary secretion[85105106]

The slowing of gut motility also allows more time forwater absorption A decrease in fecal volume has anegative effect on motility as the intrinsic reflexes thatresult in propulsive contractions are dependent onmechanoreceptor activation [85]

Opioids Increase Sphincter Tone Which May CauseSymptoms Such as Sphincter of Oddi Spasms andDifficult Defecation

Comment The effect of opioids on the lower esopha-geal sphincter in humans remains unclear Most volun-teer studies have shown an increase in resting pressurebut an abnormal coordination [107108] In patients withreflux morphine was shown to reduce the number oftransient sphincter relaxations but in some experimentsthere was an increased incidence of gastro-esophagealreflux [109110] However many of the studies wereflawed by methodological limitations New devices suchas the functional lumen imaging probe (EndoFLIP) mayclarify how opioids interfere with esophageal function[111]

The effect on the pylorus was investigated by Stacheret al (1992) who documented increased tone whichwill invariably worsen gastro-esophageal reflux [112]

Morphine administration results in sphincter of Oddicontractions leading to a decreased emptying of pan-creatic juice and bile and therefore delayed digestion[113] It has been observed that patients on opioid ther-apy may experience acute biliary pain attacks [114115]Opioid-induced sphincter of Oddi dysfunction has alsobeen described in patients addicted to opioids present-ing findings such as pancreatobiliary pain and dilation ofthe bile duct [68]

The ileal brake has only been investigated in animalstudies where it was shown that endogenous opioidscontribute to the stomach-to-caecum transit [116]

Opioid-induced dysfunction of the ano-rectal physiologyis particularly relevant as sphincter dysfunction can resultin straining hemorrhoids andor incomplete evacuation

which are worsened by constipation The significance ofanal sphincter dysfunction in OIBD has only beensparsely assessed [69] but preclinical studies indicatethat opioids not only inhibit relaxation of the internal analsphincter but also the detection of stool in the upperanal canal [117118] This is in line with a recent study ofpatients treated with opioid analgesics where one-thirdof patients had feeling of anal blockage [30]

Opioid Antagonists Counteract the Effects ofOpioids in the Human Gut on Motility FluidTransport and Sphincter Function

Comment Antagonism of l-receptors has been shownto reverse the effect of opioids on gut motility in numer-ous animal studies [89119120] In humans opioid an-tagonists reversed the effect of opioids on theesophagus and stomach and increased gut motility inthe intestine [64110121ndash125] It should be noted thatsome studies found no effect of opioid antagonists(eg on motility in the stomach and small intestine) butthis may be explained by methodological limitations[9097] Consistent with the physiological experimentspilot clinical studies have shown that naloxone can im-prove chronic idiopathic gastric stasis ldquonormalrdquo consti-pation and chronic idiopathic pseudoobstruction[100126ndash128]

Preclinical studies have shown that antagonists of d-re-ceptors reverse the effects of opioids on secretion[113] However there is a lack of human physiologicalstudies the effect of antagonists on secretion has notbeen addressed although relief of evacuation problemsdue to dry feces is frequently reported [129]

Opioid antagonists were shown to eliminate the effect ofopioids on sphincter function in preclinical studies [114]In humans the effect of morphine and pethidine onsphincter of Oddi contractions was also reduced by na-loxone [130]

QoL Can Be Worse due to Side Effects of Opioids

Comment Patients with moderate-to-severe pain whoreceive opioid analgesic treatment for their pain oftenexperience a secondary burden due to the adverse ef-fects of opioids (for example OIC) [59131]

Many of the adverse events associated with opioid anal-gesics may subside due to tolerance However thesymptoms of OIC often persist for some time resultingin a significant impact on patientsrsquo QoL [59] In patientstaking opioids constipation may be more distressing forthe patient than the underlying pain In a large interna-tional survey of patients treated with opioid therapies forsix or more months patients suffering from constipationwere more likely to visit their physician take time off

work and feel that their work productivity and their cap-ability of performing daily activities was impaired com-pared with those who did not experience constipation[83]

Assessment of QoL in Patients with OICOIBD Can

Assist Therapeutic Choices

Comment As reviewed recently numerous assessmenttools both generic (such as SF-36EQ5D etc) andconstipation specific (such as PAC-QoL) are used toassist therapeutic choices and evaluate QoL in consti-pated patients in general and in patients with OICOIBDin particular [132] One special type of general QoLmeasure is the utility value which is usually measuredbetween 0 and 1 where perfect health is given a scoreof 1 A number of studies have shown a reduction inQoL as a result of constipation A study of patients whowere treated with opioid analgesics and had a severenoncurable disease and relatively short life expectancyused the EuroQoL five-dimension questionnaire (EQ-5D)to measure QoL The EQ-5D score in patients withoutadvanced illness who did not experience constipationwas much higher (065) than the score for patients withconstipation (031) [27] In a study on QoL in patientswith chronic functional constipation a cost-effectivenessmodel that measured health outcomes by number ofquality-adjusted life-years demonstrated a small 1health benefit for one laxative over another [133]

Nonpharmacological Prevention and Treatment of OIC

Nonpharmacological Treatments of OIC Include

Dietary Recommendations and Lifestyle

Modifications

Comment In patients with OIC no study in the currentliterature has tested the efficacy of nonpharmacologicaltreatments In subjects with chronic idiopathic constipa-tion there is no evidence that increasing fluid intakeunless there is co-existent dehydration is an effectivetreatment

In nonopioid-induced constipation (ie chronic idio-pathic constipation) increasing soluble dietary fiberpsyllium or ispaghula may improve symptoms[134135] Finally moderate-to-intense physical activitymay improve moderate chronic idiopathic constipation[134] With regard to OIC standard daily fluid and fiberintakes should be recommended although this is notevidence based However increases in physical activitymight be difficult to obtain in patients with chronic painrequiring treatment with opioids

If narcotic bowel syndrome is suspected to contributeto the symptoms tapering or withdrawal of opioidsshould be tried and pain should be treated by alterna-tive measures [136]

Pharmacological Prevention and Treatment of OICOIBD

The Choice of a Laxative to Treat OICOIBDDepends on the Perceived Efficacy and thePreference of the Patient Indirect Evidence FavorsBisacodyl Sodium Picosulfate Macrogol(Polyethelene Glycol) and Sennosides as FirstChoice

Comment Both bisacodyl (and its derivative sodiumpicosulfate) and sennosides stimulate secretion and arevery potent prokinetics in the colon Their prokinetic ac-tion may potentially also be active in the more oral seg-ments of the gut [137ndash139] Bisacodyl is used as therescue laxative in most of the therapeutic trials for OICand the amount taken is considered a sensitive variablefor the efficacy of the drug under investigation [32ndash3443140ndash142] Macrogol and sugars such as lactu-lose act by binding water Macrogol and lactuloseproved to be significantly superior to placebo macrogolbeing numerically better than lactulose (Table 1) [142]

When the choice of the rescue laxative was decided byOIC patients in one study approximately 80ndash90 of pa-tients preferred a ldquostimulant laxativerdquo (bisacodyl orsenna) [22] whereas in another study macrogol and so-dium picosulfate were the preferred laxatives [147]Hence bisacodyl sodium picosulfate sennosides andmacrogol appear to have similar efficacy in OIC [147]

Preventive administration of laxatives to 720 adultJapanese patients treated with oral opioid analgesics forthe first time was effective in preventing OIC (defined asa stool-free interval of72 hours) The most frequentlyprescribed laxatives were magnesium oxide and sennaThere were no apparent differences in the efficacy be-tween laxatives [148]

Of importance is that many patients are not informed (ordo not recall that they have been informed) about con-stipation and laxatives when opioids are prescribedHence in a recent interview study at the pharmacy withpatients having their first opioid prescription only 28remembered having received information about the riskof constipation and 13 were prescribed laxatives orinstructed to request them [149]

Sugars and Sugar Alcohols Such as LactuloseLactose and Sorbitol Should Not Be Used toPrevent or Treat OIC

Comment Metabolism of sugars and sugar alcohols bythe intestinal microbiota leads to short chain carbonicacids and gas The ensuing abdominal distension mayaggravate distension in OIBD [150151] Lactulose andpolyethylene glycol were studied in a controlled trial thatcomprised of 308 critically ill patients with multipleorgan failure and mechanical ventilation Intestinal

aldesig

rvention

variable

Results

Random

double

cebo-c

tenance

self-d

efined

constipation

col3350e

Baselin

Random

inally

patients

self-d

efined

12ndash48

15ndash60

cation-f

rval72-h

period

xative

Random

cebo-c

double

hopedic

patients

self-p

1additio

(ldquo2

capsule

srdquo)

Change

2(Pfrac14

Random

ddouble

noncancer

patients

additio

nalsym

ecrite

Change

Random

cebo-c

double

noncancer

patients

1additio

ecrite

Responder

(Pfrac14

al2015

(continued)

aldesig

rvention

variable

Results

Random

double

noncancer

patients

ldquocle

patients

baselin

Results

BIDfrac14

edaily

ICfrac14

id-induce

dconstipation

Mfrac14

sponta

induced

additi

onalla

xative

Mfrac14

aldesig

rvention

Results

Random

ddouble

epatients

noncancer

ldquowith

equency

idusage

xone-t

patients

frequency

patient

3patients

experienced

rsalof

random

lleltr

patients

noncancer

ldquowith

longed-r

oxycodonen

longed-r

oxycodonep

lacebo

random

findin

cebo-c

lleltr

patients

cancer

ldquowith

concom

constipationrdquo

oxycodone

ependent

random

cebo-c

lleltr

patients

noncancer

longed-r

oxycodone

60ndash80

longed-r

oxycodonep

lacebo

reduced

in2009

random

cebo-c

lleltr

patients

modera

cancer

longed-r

oxycodone)

longed-r

oxycodonep

lacebo

laxative

innalo

edzai2012

[3353]

Ifrac14B

Function

OICfrac14

dconstipation

Mfrac14

sponta

induce

additi

laxative

Mfrac14

TIDfrac14

xegolfo

rvention

Results

random

dose-f

cebo-c

llelgro

patients

cancer-

xegol(5

nchange

baselin

(Pfrac14

Webste

enticalphase

random

double

llelgro

atients

noncancer

response

final4

weeks)

(Pfrac14

inboth

random

llelgro

patients

noncancer

xegol25

0ndash10

eequiv

Long-t

rabili

occurr

frequently

inalpain

nausea

headache

Webste

AEfrac14

Mfrac14

sponta

induced

additi

onalla

xative

OCfrac14

ylnaltr

aldesig

rvention

variable

Results

tochro

respective

Laxation

response

-coecal

transit

patients

treate

xation

response

-coecaltr

random

cebo-c

double

patients

illness

within

4hours

treatm

Laxation

within

4hours

respective

Random

double

cebo-c

patients

illness

laxative

treatm

initia

4hours

response

respective

ly(Pfrac14

patients

report

laxative

Random

cebo-c

patients

noncancer

ctions

leadin

within

4hours

within

4hours

(daily

altern

respective

(continued)

aldesig

rvention

variable

Results

random

double

llel-gro

cebo-c

patients

hopedic

cedure

likely

ization

Once-d

laxation

patients

experiencin

laxation

within

4hours

Laxation

within

2hours

(Pfrac14

4hours

(Pfrac14

laxation

(Pfrac14

OICfrac14

id-induce

dconstipation

Mfrac14

sponta

induced

additi

onalla

xative

Cfrac14

subcuta

aldesig

rvention

variable

Results

Random

cebo-c

double

patients

(Nfrac14

iddependence

(Nfrac14

imopan

patients

within

8hours

patients

8hours

imopan

respective

random

cebo-c

double

noncancer

imopan

Change

imopan

(thorn17

imopan

ID(thorn

imopan

ID(thorn

Webste

random

cebo-c

double

patients

noncancer

imopan

patients

inbaselin

imopan

Jansen

Random

cebo-c

double

patients

noncancer

imopan

patients

sponders

inboth

imopan

tistically

BIDfrac14

edaily

ICfrac14

id-induce

dconstipation

QIDfrac14

Mfrac14

sponta

induce

additi

onalla

xative

pseudo-obstruction or Ogilviersquos syndrome occurred in55 of patients in the lactulose group and in 10 ofpatients in the macrogol group [152] Lactulose seemssimilarly effective to treat OIC as senna [144] thoughnumerically inferior to macrogol (Table 1) [143] and itshould therefore not be considered first choice

Gastro-Oesophageal Reflux Symptoms as Part of

OIBD Should Be Treated like Primary Reflux

Disease

Comment There are no published therapeutic trials ongastro-esophageal reflux as part of OIBD but there isno reason to assume that conventional reflux treatmentcould not ameliorate reflux symptoms in OIBD

Patients with Nausea Secondary to Opioid

Treatment Should Be Offered Dopamine

Antagonists

Comment Published evidence shows no or only minorpositive effects of metoclopramide on nausea and vom-iting when morphine was given parenterally in acutepain [153154] However when given for chronic painpositive results on nausea were reported in an uncon-trolled study [155] Data on the neurokinin-1-receptor-

antagonist aprepitant are insufficient to recommend itsuse [156]

Treatment of OIC with New Laxatives (Prucalopride

Lubiprostone) May Be Promising However to Date

There Are Insufficient Data to Warrant Such

Treatments in OIC Patients

Comment In recent years a few new drugs have beenproposed for the medical treatment of patients withchronic constipation [157] Among these prucalopride(a potent and highly selective agonist of 5-HT4 serotoninreceptors) [158] and lubiprostone (a chloride [Cl-] chan-nel activator derived from prostaglandin E1) [159] arecurrently sold in Europe and the United States respect-ively Both these drugs have also been tested in pa-tients complaining of OIC (Table 1) Concerningprucalopride there is only one published study availableshowing that both the 2 mg and 4 mg once-daily dosessignificantly increase spontaneous bowel movements inthese patients but only during the first two weeks oftreatment [29] Concerning lubiprostone the availabledata (two published studies [142145] and four ab-stracts [38404144]) seem to suggest that the drugmay be useful in the treatment of OIC even though it ispossible that this effect is limited to some subtypes ofpatients Compared with placebo lubiprostone wasable to improve symptoms related to OIC [142] Another

Figure 2 Treatment guidance algorithm for patients initiating opioid treatment and patients presenting with OICPatients with previous constipation not responding well to laxatives and given an opioid therapy on top are probablybest treated with an agonist-antagonist plus a laxative First choice laxativesmdashbisacodyl sodium picosulfate sennamacrogol OIC frac14 opioid-induced constipation

study showed no advantage over the less expensivesenna [145]

Peripherally Acting l-Opioid Receptor Antagonists

Peripherally Acting l-Opioid Receptor AntagonistsEffectively Reduce OIC

Comment Attempts have been made to develop opioidantagonists that block peripheral opioid receptors andreduce OIC They do not have access to opioid recep-tors within the central nervous system and thereforespare central analgesic opioid function Sixteen RCTson the following four peripherally acting l-opioid recep-tor antagonists (PAMORAs) have been identified nalox-one (either alone or in fixed-ratio combination withoxycodone) methylnaltrexone naloxegol and alvimo-pan On the whole they provide evidence for efficacy ofPAMORAs for OIC and partly also for OIBD [160]

In Patients with Chronic Cancer or Noncancer PainProlonged-Release NaloxoneOxycodoneCombination Effectively Reduces OIC WhileMaintaining Equal Analgesia to Prolonged-ReleaseOxycodone Alone

Comment Following oral administration naloxone hasnearly no systemic bioavailability due to extensive first-pass hepatic metabolism [161] Therefore it acts almostexclusively on opioid receptors in the GI tract andspares central analgesia Prolonged-release (PR) nalox-oneoxycodone combination was tested in four RCTs in974 patients with chronic pain [182335160]Oxycodone dose per 24 hours ranged between 40 mgand 120 mg and trial duration from four to 12 weeksOxycodonenaloxone (21 fixed ratio)-treated patientsexhibited improved BFI the primary outcome in all stud-ies compared with those treated by oxycodoneplacebo(mean difference ranged from 111 to 175 pointsacross studies) (Table 2) No serious adverse eventswere reported Notably one RCT tested the effect of2 mg or 4 mg of naloxone (not prolonged release) aloneor placebo in nine patients taking stable doses of opi-oids who had OIC [13] Oral naloxone-treated patientshad some improvement in bowel frequency but reversalof analgesia was experienced by three of the ninepatients

Oral Naloxegol Is Effective and Safe in ReducingOIC in Patients with Chronic Pain

Comment Naloxegol a PEGylated derivative of nalox-one is taken orally and is not transported across theblood-brain barrier Results of three trials in more than1500 patients show that at a daily dose of 25 mg thenumber of days per week with spontaneous and normalbowel movements increased significantly compared withplacebo (Table 3) Pain intensities and opioid

requirements did not change and no withdrawal symp-toms or serious cardiovascular events were observed[4243] The advantage of the drug is that it can beused orally in the community regardless of the opioidtaken by the patient

Methylnaltrexone Injections Can Effectively RelieveOIC in Patients with Postoperative Cancer andNoncancer Chronic Pain

Comment Due to its chemical structure methylnaltrex-one does not cross the blood-brain barrier and actsonly peripherally The five identified RCTs in this cat-egory (gt800 patients) varied considerably in terms ofnumber of randomized patients (22 to 460) treatmentduration (single dose to four weeks) diagnosis (cancerpain chronic noncancer pain methadone maintenance)and dose (015 mgkg 030 mgkg or 12 mg adminis-tered daily or every other day intravenously or by sub-cutaneous injection) [1222253436] The outcome inmost studies was either time to first bowel movementafter the injection or more commonly the percentageof patients achieving bowel movement within two tofour hours of treatment All studies showed significantlybetter outcome with methylnaltrexone compared withplacebo (Table 4) Secondary outcomes such asdecreased laxative use also improved The treatmentwas generally well tolerated although cases of GI per-foration in association with methylnaltrexone use havebeen reported [163] Recent findings suggest that meth-ylnaltrexone can lead to increased morphine demandsfor postoperative pain control [164]

Alvimopan Is Approved in the United States for Usein Hospitalized Patients for Preventing orDecreasing the Course of Postoperative Ileus AfterBowel Resection Long-Term Safety StudiesIndicated that It May Possibly Increase the Risk ofCardiovascular Events There Is Some Evidencethat Alvimopan Reduces OIC in Subjects withChronic Opioid Intake

The selective peripheral action of alvimopan is related toits large molecular size and zwitter-ionic form FourRCTs studied alvimopan in OIC in more than 1500 pa-tients for preventing or decreasing the course ofpostoperative ileus after bowel resection (Table 5) Twoof them showed a significant improvement in the num-ber of patients demonstrating bowel movements thenumber of bowel movements andor reduced durationof time to first bowel movement [1519] However theprimary end point of three spontaneous bowel move-ments per week in two other studies was not [32] orwas only partly met [33] Notably opioid-naıve patientswith ldquoacute OICrdquo need much higher doses of alvimopan(12 mg) to reduce the length of postoperative ileus afterbowel surgery than patients with chronic opioid treat-ment (1ndash2 mg) [165]

Three other PAMORAs are being developed for OIC[47166] bevenopran (Cubist Pharmaceuticals) TD-1211 (Theravance South San Francisco CA USA) andnaldemedine (S-297995 Shionogi Osaka Japan) Anoral form of methylnaltrexone is also under developmentfor treating OIC in patients on opioid therapy for chronicnoncancer pain Clinical RCT data are not available

Both Laxatives and Opioid Antagonists for OICHave Benefits on QoL

Comment In the trials evaluating a fixed combination ofprolonged-release oxycodonenaloxone bowel functionand QoL were investigated using the BFI and other toolsIn the three phase III trials performed with the majority ofpatients with moderate-to-severe nonmalignant pain sig-nificant improvements in constipation were observed inpatients taking PR oxycodonenaloxone compared withthose taking PR oxycodone The improvement in consti-pation was generally seen within one week of treatmentand lasted the duration of the trials [1823] In anassessment of PR oxycodonenaloxone using the QoLtool SF-36 significant improvements were observed inthe subscales of social functioning vitality and generalhealth at week 12 of treatment [167]

A large noninterventional study of clinical practiceobserved improvements in QoL for PR oxycodonenaloxone-treated patients Patients with severe chronicpain of various etiologies treated with PR oxycodonenaloxone demonstrated significant reductions in consti-pation in both opioid-naıve and opioid-tolerant patients[168] The Short-Form Brief Pain Inventory demon-strated an improvement of 43 (in 2023 patients) afterfour weeks of treatment [168]

In an RCT both senna and lubiprostone improved QoLand constipation-related symptoms in OIC in postopera-tive orthopedic patients treated with opioids with nosignificant between-group differences [158]

Noncancer patients taking prucalopride reported agreater improvement in their constipation severity andthe efficacy of treatment than patients taking placeboas measured by the patient-reported PAC-SYM andPAC-QoL questionnaires (patient assessment of consti-pation symptoms and patient assessment of constipa-tion symptoms and quality of life respectively) [140]However the effect was only significant during the firsttwo weeks of treatment

Patients with OIC treated with 25 mg naloxegol oncedaily a peripherally acting l-opioid receptor antagonistreported improved median total patient-reported scoreson the PAC-QoL questionnaire compared with patientstaking placebo During the double-blind treatmentperiod the 25 mg naloxegol group reported a statistic-ally significant improvement in SF-36 scale scores formental health social functioning physical functioning

and vitality compared with patients receiving placeboThere was no significant difference between placeboand the 5 mg and 50 mg naloxegol dose groups [42]

Summary and Conclusions

OIBD is an increasing problem due to the wider use ofopioids including the treatment of nonmalignant painCurrent knowledge is certainly insufficient regardingmany aspects of OIC and more so of OIBD as reflectedby our votes regarding the level of evidence (Appendix)Though this holds particularly true for the managementof the opioid side effects on the upper GI tract recom-mendations can be derived from what we know at pre-sent (Figure 2) As only about half of the patients takingopioid experience OIC a general comedication with alaxative or an opiate antagonist would be an overtreat-ment Rather awareness of the problem is mandatoryfor the treating physician In addition prophylaxis couldbe adjusted to the perceived risks of OiC in a particularpatient for example it could be prescribed to thosewho have had constipation as a problem before startingopioids However this issue deserves further study inthe future

The conventional laxatives bisacodyl sodium picosul-fate macrogol and senna seem to be the first choiceto treat OIC The new laxatives linaclotide lubiprostoneand prucalopride may also be effective in selected pa-tients but do not seem to be superior to PAMORAsbased on the presently available indirect comparisonsPAMORAs clearly have a proven effect on OIC WhetherPAMORAs have advantages over laxatives through theaddressing of OIBD and not only OIC needs to beshown in randomized double-blind comparative trials

Acknowledgments

Editorial assistance was provided by Ogilvy ClinicalSciences London

References1 Katz N The impact of pain management on quality

of life J Pain Symptom Manage 200224S38ndash47

2 Trescot AM Glaser SE Hansen H et al

Effectiveness of opioids in the treatment of chronic

non-cancer pain Pain Physician 200811S181ndash200

3 Dart RC Surratt HL Cicero TJ et al Trends in opi-

oid analgesic abuse and mortality in the United

States N Engl J Med 2015372241ndash8

4 Pappagallo M Incidence prevalence and manage-

ment of opioid bowel dysfunction Am J Surg 2001

182S11ndash8

5 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 20034231ndash56

6 Klepstad P Borchgrevink PC Kaasa S Effects on

cancer patientsrsquo health-related quality of life after the

start of morphine therapy J Pain Symptom Manage

20002019ndash26

7 Camilleri M Opioid-induced constipation

Challenges and therapeutic opportunities Am J

Gastroenterol 2011106835ndash42

8 Rachinger-Adam B Conzen P Azad SC

Pharmacology of peripheral opioid receptors Curr

Opin Anaesthesiol 201124408ndash13

9 Keefer L Drossman DA Guthrie E et al Centrally

mediated disorders of gastrointestinal pain

Gastroenterology 20161501408ndash19

10 Panchal SJ Muller-Schwefe P Wurzelmann JI

Opioid-induced bowel dysfunction Prevalence

pathophysiology and burden Int J Clin Pract 2007

611181ndash7

11 Coluzzi F Pappagallo M Opioid therapy for chronic

noncancer pain Practice guidelines for initiation and

maintenance of therapy Minerva Anestesiol 2005

71425ndash33

12 Yuan CS Foss JF OrsquoConnor M et al

Methylnaltrexone for reversal of constipation due to

chronic methadone use A randomized controlled

trial JAMA 2000283367ndash72

13 Liu M Wittbrodt E Low-dose oral naloxone reverses

opioid-induced constipation and analgesia J Pain

Symptom Manage 20022348ndash53

14 Cowan DT Wilson-Barnett J Griffiths P Allan LG A

survey of chronic noncancer pain patients pre-

scribed opioid analgesics Pain Med 20034340ndash51

15 Paulson DM Kennedy DT Donovick RA et al

Alvimopan An oral peripherally acting mu-opioid

receptor antagonist for the treatment of opioid-

induced bowel dysfunctionmdasha 21-day treatment-

randomized clinical trial J Pain 20056184ndash92

16 Gray D Spence D The prevalence of constipation

in patients receiving methadone maintenance treat-

ment for opioid dependency J Sub Use 2005

10397ndash401

17 Cook SF Lanza L Zhou X et al Gastrointestinal

side effects in chronic opioid users Results from a

population-based survey Aliment Pharmacol Ther2008271224ndash32

18 Simpson K Leyendecker P Hopp M et al Fixed-ratio combination oxycodonenaloxone comparedwith oxycodone alone for the relief of opioid-inducedconstipation in moderate-to-severe noncancer painCurr Med Res Opin 2008243503ndash12

19 Webster L Jansen JP Peppin J et al Alvimopan aperipherally acting mu-opioid receptor (PAM-OR) an-tagonist for the treatment of opioid-induced boweldysfunction Results from a randomized double-blind placebo-controlled dose-finding study in sub-jects taking opioids for chronic non-cancer painPain 2008137428ndash40

20 Bell TJ Panchal SJ Miaskowski C et al The preva-lence severity and impact of opioid-induced boweldysfunction Results of a US and European PatientSurvey (PROBE 1) Pain Med 20091035ndash42

21 Candrilli SD Davis KL Iyer S Impact of constipationon opioid use patterns health care resource utiliza-tion and costs in cancer patients on opioid therapyJ Pain Palliat Care Pharmacother 200923231ndash41

22 Chamberlain BH Cross K Winston JL et alMethylnaltrexone treatment of opioid-induced con-stipation in patients with advanced illness J PainSymptom Manage 200938683ndash90

23 Lowenstein O Leyendecker P Hopp M et alCombined prolonged-release oxycodone and nalox-one improves bowel function in patients receivingopioids for moderate-to-severe non-malignantchronic pain A randomised controlled trial ExpOpin Pharmacother 200910531ndash43

24 Meissner W Dohrn B Reinhart K Enteral naloxonereduces gastric tube reflux and frequency of pneu-monia in critical care patients during opioid anal-gesia Crit Care Med 200331776ndash80

25 Slatkin N Thomas J Lipman AG et alMethylnaltrexone for treatment of opioid-inducedconstipation in advanced illness patients J SupportOncol 2009739ndash46

26 Hjalte F Berggen AC Bergendahl H Hjortsberg C Thedirect and indirect costs of opioid-induced constipationJ Pain Symptom Manage 201040696ndash703

27 Penning-van Beest FJ van der Haak P Klok RMet al Quality of life in relation to constipation amongopioid users J Med Econ 201013129ndash35

28 Rosti G Gatti A Costantini A Sabato AF Zucco FOpioid-related bowel dysfunction Prevalence and

identification of predictive factors in a large sampleof Italian patients on chronic treatment Eur RevMed Pharmacol Sci 2010141045ndash50

29 Sloots CE Poen AC Kerstens R et al Effects ofprucalopride on colonic transit anorectal functionand bowel habits in patients with chronic constipa-tion Aliment Pharmacol Ther 200216759ndash67

30 Tuteja AK Biskupiak J Stoddard GJ Lipman AGOpioid-induced bowel disorders and narcotic bowelsyndrome in patients with chronic non-cancer painNeurogastroenterol Motil 201022424ndash30

31 Wee B Adams A Thompson K et al How muchdoes it cost a specialist palliative care unit to man-age constipation in patients receiving opioid therapyJ Pain Symptom Manage 201039644ndash54

32 Irving G Penzes J Ramjattan B et al A random-ized placebo-controlled phase 3 trial (study SB-767905013) of alvimopan for opioid-induced boweldysfunction in patients with non-cancer pain J Pain201112175ndash84

33 Jansen JP Lorch D Langan J et al A randomizedplacebo-controlled phase 3 trial (Study SB-767905012) of alvimopan for opioid-induced bowel dys-function in patients with non-cancer pain J Pain201112185ndash93

34 Michna E Blonsky ER Schulman S et alSubcutaneous methylnaltrexone for treatment ofopioid-induced constipation in patients with chronicnonmalignant pain A randomized controlled studyJ Pain 201112554ndash62

35 Ahmedzai SH Nauck F Bar-Sela G et al Arandomized double-blind active-controlled double-dummy parallel-group study to determine the safetyand efficacy of oxycodonenaloxone prolonged-release tablets in patients with moderateseverechronic cancer pain Palliat Med 20122650ndash60

36 Anissian L Schwartz HW Vincent K et alSubcutaneous methylnaltrexone for treatment ofacute opioid-induced constipation Phase 2 study inrehabilitation after orthopedic surgery J Hosp Med2012767ndash72

37 Abramowitz L Beziaud N Labreze L et alPrevalence and impact of constipation and boweldysfunction induced by strong opioids A cross-sectional survey of 520 patients with cancer painDYONISOS study J Med Econ 2013161423ndash33

38 Cryer B Mareya S Joswick T et al Spontaneousbowel movement frequency is improved over 12weeks of lubiprostone therapy in opioid-induced

constipation patients regardless of gender age orrace Pooled analysis of three well-controlled stud-ies Am J Gastroenterol 2013108S567

39 Ivanova JI Birnbaum HG Yushkina Y et al Theprevalence and economic impact of prescriptionopioid-related side effects among patients withchronic noncancer pain J Opioid Manage 20139239ndash54

40 Joswick T Mareya SM Lichtlen P Woldegeorgis FUeno R Time to onset of lubiprostone treatment ef-fect in chronic non-cancer pain patients with opioid-induced constipation Data from two phase 3randomized double-blind placebo-controlled trialsGastroenterology 2013144S540

41 Mareya S Drossman D Joswick T et alLubiprostone effectively relieves opioid-induced con-stipation in patients using on-diphenylheptane opi-oids for non-cancer pain Pooled analysis of threerandomized controlled trials Gastroenterology 2013144S539ndash40

42 Webster L Dhar S Eldon M et al A phase 2double-blind randomized placebo-controlled dose-escalation study to evaluate the efficacy safety andtolerability of naloxegol in patients with opioid-induced constipation Pain 20131541542ndash50

43 Chey WD Webster L Sostek M et al Naloxegol foropioid-induced constipation in patients with non-cancer pain N Engl J Med 20143702387ndash96

44 Spierings EL Drossman DA Cryer BL Losch-Beridon T Ueno R A pooled analysis of responseto lubiprostone in patients with opioid induced con-stipation receiving non-methadone opioids versusmethadone Gastroenterology 2014146S360

45 Ebell MH Siwek J Weiss BD et al Strength of rec-ommendation taxonomy (SORT) A patient-centeredapproach to grading evidence in the medical litera-ture Am Fam Physician 200469548ndash56

46 Balshem H Helfand M Schunemann HJ et alGRADE guidelines 3 Rating the quality of evidenceJ Clin Epidemiol 201164401ndash6

47 Camilleri M Drossman DA Becker G et alEmerging treatments in neurogastroenterology Amultidisciplinary working group consensus statementon opioid-induced constipation NeurogastroenterolMotil 2014261386ndash95

48 Gaertner J Siemens W Camilleri M et alDefinitions and outcome measures of clinical trialsregarding opioid-induced constipation A systematicreview J Clin Gastroenterol 2015499ndash16

49 Brock C Olesen SS Olesen AE et al Opioid-induced bowel dysfunction Pathophysiology andmanagement Drugs 2012721847ndash65

50 Zhong F Christianson JA Davis BM Bielefeldt KDichotomizing axons in spinal and vagal afferentsof the mouse stomach Dig Dis Sci 200853194ndash203

51 Knowles CH Aziz Q Basic and clinical aspects ofgastrointestinal pain Pain 2009141191ndash209

52 Lottrup C Olesen SS Drewes AM The pain systemin oesophageal disorders Mechanisms clinicalcharacteristics and treatment Gastroenterol ResPract 20112011910420

53 Arendt-Nielsen L Laursen RJ Drewes AM Referredpain as an indicator for neural plasticity Prog BrainRes 2000129346ndash56

54 Drewes AM Arendt-Nielsen L Jensen JH et alExperimental pain in the stomach A model basedon electrical stimulation guided by gastroscopy Gut199741753ndash7

55 Brinkert W Dimcevski G Arendt-Nielsen L DrewesAM Wilder-Smith OHG Dysmenorrhoea is associ-ated with hypersensitivity in the sigmoid colon andrectum Pain 2007132S46ndash51

56 Froslashkjaeligr JB Andersen SD Gale J et al An experi-mental study of viscero-visceral hyperalgesia usingan ultra-sound-based multimodal sensory testingapproach Pain 2005119191ndash200

57 Brock C Andresen T Froslashkjaeligr JB et al Centralpain mechanisms following combined acid and cap-saicin perfusion of the human oesophagus Eur JPain 200914273ndash81

58 Sami SA Rossel P Dimcevski G et al Corticalchanges to experimental sensitization of the humanesophagus Neuroscience 2006140269ndash79

59 Holzer P Ahmedzai SH Niederle N et al Opioid-induced bowel dysfunction in cancer-related painCauses consequences and a novel approach forits management J Opioid Manag 20095145ndash51

60 Olesen AE Drewes AM Validated tools for evaluat-ing opioid-induced bowel dysfunction Adv Ther201128279ndash94

61 Rentz AM Yu R Muller-Lissner S Leyendecker PValidation of the Bowel Function Index to detectclinically meaningful changes in opioid-induced con-stipation J Med Econ 200912371ndash83

62 Kulich KR Madisch A Pacini F et al Reliability andvalidity of the Gastrointestinal Symptom RatingScale (GSRS) and Quality of Life in Reflux andDyspepsia (QOLRAD) questionnaire in dyspepsia Asix-country study Health Qual Life Outcomes 2008612

63 Scott SM Manometric techniques for the evaluationof colonic motor activity Current statusNeurogastroenterol Motil 200315483ndash513

64 Smith K Hopp M Mundin G et al Naloxone aspart of a prolonged release oxycodonenaloxonecombination reduces oxycodone-induced slowing ofgastrointestinal transit in healthy volunteers ExpertOpin Investig Drugs 201120427ndash39

65 Wallon C Braaf Y Wolving M Olaison GSoderholm JD Endoscopic biopsies in Ussingchambers evaluated for studies of macromolecularpermeability in the human colon Scand JGastroenterol 200540586ndash95

66 Marciani L Garsed KC Hoad CL et al Stimulationof colonic motility by oral PEG electrolyte bowelpreparation assessed by MRI Comparison of splitvs single dose Neurogastroenterol Motil 2014261426ndash36

67 Sandberg TH Nilsson M Poulsen JL et al A novelsemi-automatic segmentation method for volumetricassessment of the colon based on magnetic reson-ance imaging Abdom Imaging 2015402232ndash41

68 Sharma SS Sphincter of Oddi dysfunction in pa-tients addicted to opium An unrecognized entityGastrointest Endosc 200255427ndash30

69 Sun WM Read NW Verlinden M Effects of lopera-mide oxide on gastrointestinal transit time and ano-rectal function in patients with chronic diarrhoea andfaecal incontinence Scand J Gastroenterol 19973234ndash8

70 Alqudah M Gregersen H Drewes AM McMahonBP Identification of component muscle function inthe ano-rectal region of healthy controls usingEndoFLIP distension Neurogastroenterol Motil201224e591ndash9

71 Carrington EV Brokjaer A Craven H et alTraditional measures of normal anal sphincter func-tion using high-resolution anorectal manometry(HRAM) in 115 healthy volunteersNeurogastroenterol Motil 201426625ndash35

72 Matsumoto AK Babul N Ahdieh H Oxymorphoneextended-release tablets relieve moderate to severe

pain and improve physical function in osteoarthritis

Results of a randomized double-blind placebo-and active-controlled phase III trial Pain Med 20056357ndash66

73 Kalso E Edwards JE Moore RA McQuay HJOpioids in chronic non-cancer pain Systematic re-

view of efficacy and safety Pain 2004112372ndash80

74 Afilalo M Morlion B Efficacy of tapentadol ER formanaging moderate to severe chronic pain Pain

Physician 20131627ndash40

75 Buynak R Shapiro DY Okamoto A et al Efficacy

and safety of tapentadol extended release for themanagement of chronic low back pain Results of a

prospective randomized double-blind placebo-and active-controlled Phase III study Expert OpinPharmacother 2010111787ndash804

76 Steigerwald I Schenk M Lahne U et alEffectiveness and tolerability of tapentadol prolonged

release compared with prior opioid therapy for themanagement of severe chronic osteoarthritis painClin Drug Investig 201333607ndash19

77 Wild JE Grond S Kuperwasser B et al Long-termsafety and tolerability of tapentadol extended release

for the management of chronic low back pain orosteoarthritis pain Pain Pract 201010416ndash27

78 Staats PS Markowitz J Schein J Incidence of con-

stipation associated with long-acting opioid therapyA comparative study South Med J 2004

97129ndash34

79 Kress HG Von der Laage D Hoerauf KH et al Arandomized open parallel group multicenter trial to

investigate analgesic efficacy and safety of a newtransdermal fentanyl patch compared to standard

opioid treatment in cancer pain J Pain SymptomManage 200836268ndash79

80 Wolff RF Aune D Truyers C et al Systematic re-

view of efficacy and safety of buprenorphine versusfentanyl or morphine in patients with chronic moder-

ate to severe pain Curr Med Res Opin 201228833ndash45

81 Breivik H Ljosaa TM Stengaard-Pedersen K et al

A 6-month randomised placebo-controlled evalu-ation of efficacy and tolerability of a low-dose 7-day

buprenorphine transdermal patch in osteoarthritispatients naıve to potent opioids Scand J Pain20101122ndash41

82 Devulder J Richarz U Nataraja SH Impact of long-term use of opioids on quality of life in patients with

chronic non-malignant pain Curr Med Res Opin2005211555ndash68

83 Bell T Annunziata K Leslie JB Opioid-induced con-stipation negatively impacts pain managementproductivity and health- related quality of lifeFindings from the National Health and WellnessSurvey J Opioid Manag 20095137ndash44

84 Holzer P Pharmacology of opioids and their effectson gastrointestinal function Am J GastroenterolSuppl 201429ndash16

85 Kurz A Sessler DI Opioid-induced bowel dysfunc-tion Pathophysiology and potential new therapiesDrugs 200363649ndash71

86 Sternini C Patierno S Selmer IS Kirchgessner AThe opioid system in the gastrointestinal tractNeurogastroenterol Motil 2004163ndash16

87 McKay JS Linaker BD Turnberg LA Influence ofopiates on ion transport across rabbit ileal mucosaGastroenterology 198180279ndash84

88 Bagnol D Mansour A Akil H Watson SJ Cellularlocalization and distribution of the cloned mu andkappa opioid receptors in rat gastrointestinal tractNeuroscience 199781579ndash91

89 Holzer P Treatment of opioid-induced gut dysfunc-tion Expert Opin Investig Drugs 200716181ndash94

90 Camilleri M Malagelada JR Stangilellini V et alDose-related effects of synthetic human and nalox-one on fed gastrointestinal motility Am J Physiol1986251147ndash54

91 Galligan JJ Akbarali HI Molecular physiology of en-teric opioid receptors Am J Gastroenterol Suppl2014217ndash21

92 Sharma SK Nirenberg M Klee WA Morphine re-ceptors as regulators of adenylate cyclase activityProc Natl Acad Sci U S A 197572590

93 Wood JD Galligan JJ Function of opioids in the en-teric nervous system Neurogastroenterol Motil20041617ndash28

94 Roy S Liu HC Loh HH mu-Opioid receptor-knockout mice The role of mu-opioid receptor ingastrointestinal transit Brain Res Mol Brain Res199856281ndash3

95 Manara L Bianchi G Ferretti P Tavani A Inhibitionof gastrointestinal transit by morphine in rats resultsprimarily from direct drug action on gut opioid sitesJ Pharmacol Exp Ther 1986237945ndash9

96 Bauer AJ Sarr MC Szurszewski JH Opioids inhibitneuromuscular transmission in circular muscle ofhuman and baboon jejunum Gastroenterol 1991101970ndash6

97 Gonenne J Camilleri M Ferber I et al Effect of alvi-mopan and codeine on gastrointestinal transit Arandomized controlled study Clin GastroenterolHepatol 20053784ndash91

98 Kraichely RE Arora AS Murray JA Opiate-inducedoesophageal dysmotility Aliment Pharmacol Ther201031601ndash6

99 Penagini R Allocca M Cantu P et al Relationshipbetween motor function of the proximal stomachand transient lower oesophageal sphincter relaxationafter morphine Gut 2004531227ndash31

100 Hawkes ND Rhodes J Evans BK et al Naloxonetreatment for irritable bowel syndrome - a random-ized controlled trial with an oral formulationAliment Pharmacol Ther 2002161649ndash54

101 Mori T Shibasaki Y Matsumoto K et alMechanisms that underlie m-opioid receptoragonist-induced constipation Differential involve-ment of m-opioid receptor sites and responsibleregions J Pharmacol Experiment Ther 201334791ndash9

102 Xu S Etropolski M Upmalis D et alPharmacokinetic and pharmacodynamic modelingof opioid-induced gastrointestinal side effects inpatients receiving tapentadol IR and oxycodone IRPharm Res 2012292555ndash64

103 Thomas J Opioid-induced bowel dysfunction JPain Symptom Manage 200835103ndash13

104 Barrett KE Keely SJ Chloride secretion by the in-testinal epithelium Molecular basis and regulatoryaspects Annu Rev Physiol 200062535ndash72

105 Kromer W Endogenous and exogenous opioids inthe control of gastrointestinal motility and secretionPharmacol Rev 198840121ndash62

106 Glad H Ainsworth MA Svendsen P Fahrenkrug JSchaffalitzky de Muckadell OB Effect of vasoactiveintestinal peptide and pituitary adenylate cyclase-activating polypeptide on pancreatic hepatic andduodenal mucosal bicarbonate secretion in the pigDigestion 20036756ndash66

107 Dowlatshahi K Evander A Walther B Skinner DBInfluence of morphine on the distal oesophagusand the lower oesophageal sphinctermdashA mano-metric study Gut 198526802ndash6

108 Drewes AM Krarup AL Olesen AE et al

Pharmacology of the esophagus Ann N Y Acad

Sci 2014132557ndash68

109 Penagini R Bartesaghi B Zannini P Negri G

Bianchi PA Lower oesophageal sphincter hyper-

sensitivity to opioid receptor stimulation in patients

with idiopathic achalasia Gut 19933416ndash20

110 Penagini R Bianchi PA Effect of morphine on

gastroesophageal reflux and transient lower

esophageal sphincter relaxation Gastroenterol

1997113409ndash14

111 McMahon BP Froslashkjaeligr JB Kunwald P et al The

Functional Lumen Imaging Probe (FLIP) for evalu-

ation of the esophagogastric junction Am J

Physiol Gastrointest Liver Physiol 2007

292G377ndash84

112 Stacher G Steinringer H Schneider C et al

Effects of the prodrug loperamide oxide lopera-

mide and placebo on jejunal motor activity Dig

Dis Sci 199237198ndash204

113 Green BT Calvin A OrsquoGrady SM Brown DR

Kinin-induced anion-dependent secretion in por-

cine ileum Characterization and involvement of

opioid- and cannabinoid-sensitive enteric neural

circuits J Pharmacol Exp Ther 2003305733ndash9

114 Coelho JCU Runkel N Herfarth C Senninger N

Effect of analgesic drugs on the electromyographic

activity of the gastrointestinal tract and sphincter of

Oddi and on biliary pressure Ann Surg 1986

20453ndash8

115 Wu S-D Zhang Z-H Jin J-Z et al Effects of nar-

cotic analgesic drugs on human Oddirsquos sphincter

motility World J Gastroenterol 2004102901ndash4

116 Brown NJ Rumsey RDE Bogentoft C Read NW

The effect of an opiate receptor antagonist on the

ileal brake mechanism in the rat Pharmacol 1993

47230ndash6

117 Burleigh DE DrsquoMello A Neural and pharmacologic

factors affecting motility of the internal anal sphinc-

ter Gastroenterol 198384409ndash17

118 Bouvier M Kirschner G Gonella J Actions of mor-

phine and enkephalins on the internal anal sphinc-

ter of the cat Relevance for the physiological role

of opiates J Auton Nerv Syst 198616219ndash32

119 Moss J Rosow CE Development of peripheral

opioid antagonists New insights into opioid ef-

fects Mayo Clin Proc 2008831116ndash30

120 Holzer P Non-analgesic effects of opioidsManagement of opioid-induced constipation byperipheral opioid receptor antagonists preventionor withdrawal Curr Pharm Des 2012186010ndash20

121 Yuan CS Foss J OrsquoConnor M Roizen M Moss JEffects of low-dose morphine on gastric emptyingin healthy volunteers J Clin Pharmacol 1998381017ndash20

122 Yuan CS Foss JF OrsquoConnor M et al Effects ofintravenous methylnaltrexone on opioid-inducedgut motility and transit time changes in subjectsreceiving chronic methadone therapy A pilot studyPain 199983631ndash5

123 Hawkes ND Richardson C Evans BK et al Effectof an enteric-release formulation of naloxone on in-testinal transit in volunteers taking codeine AlimentPharmacol Ther 200115625ndash30

124 Yuan CS Doshan H Charney MR et alTolerability gut effects and pharmacokinetics ofmethylnaltrexone following repeated intravenousadministration in humans J Clin Pharmacol 200545538ndash46

125 Netzer P Sendensky A Wissmeyer MP et al Theeffect of naloxone-3-glucuronide on colonic transittime in healthy men after acute morphine adminis-tration A placebo-controlled double-blinded cross-over preclinical volunteer study Aliment PharmacolTher 2008281334ndash41

126 Kreek MJ Schaefer RA Hahn EF Fishman JNaloxone a specific opioid antagonist reverseschronic idiopathic constipation Lancet 19831261ndash2

127 Schang JC Devroede G Beneficial effects of na-loxone in a patient with intestinal pseudoobstruc-tion Am J Gastroenterol 198580407ndash11

128 Narducci F Bassotti G Granata MT et alFunctional dyspepsia and chronic idiopathic gastricstasis Role of endogenous opiates Arch InternMed 1986146716ndash20

129 McMillan SC Assessing and managing opiate-induced constipation in adults with cancer CancerControl 2004111ndash9

130 Thune A Baker RA Saccone GTP Owen HToouli J Differing effects of pethidine and mor-phine on human sphincter of Oddi motility Br JSurg 199077992ndash5

131 Mehendale SR Yuan CS Opioid-induced gastro-intestinal dysfunction Dig Dis 200624105ndash12

132 Morlion B Clemens KE Dunlop W Quality of life

and healthcare resource in patients receiving opioidsfor chronic pain A review of the place of oxy-codonenaloxone Clin Drug Investig 2015351ndash11

133 Guest JF Clegg JP Helter MT Cost-effectivenessof macrogol 4000 compared to lactulose in the

treatment of chronic functional constipation in theUK Curr Med Res Opin 2008241841ndash52

134 Bharucha AE Pemberton JH Locke GR III

American Gastroenterological Association technicalreview on constipation Gastroenterology 2013

144218ndash38

135 Eswaran S Muir J Chey WD Fiber and functional

gastrointestinal disorders Am J Gastroenterol2013108718ndash27

136 Drossman DA Morris CB Edwards H et al

Diagnosis characterization and 3-month outcomeafter detoxification of 39 patients with narcotic

bowel syndrome Am J Gastroenterol 20121071426ndash40

137 Hardcastle JD Wilkins JL The action of senno-

sides and related compounds on human colon andrectum Gut 1970111038ndash42

138 Bassotti G Chiarioni G Germani U et alEndoluminal instillation of bisacodyl in patients withsevere (slow transit type) constipation is useful to

test residual colonic propulsive activity Digestion19996069ndash73

139 Herve S Savoye G Behbahani A et al Results of24-h manometric recording of colonic motor activ-ity with endoluminal instillation of bisacodyl in pa-

tients with severe chronic slow transit constipationNeurogastroenterol Motil 20046397ndash402

140 Sloots C Rykx A Cools M Kerstens R De Pauw MEfficacy and safety of prucalopride in patients withchronic noncancer pain suffering from opioid-induced

constipation Dig Dis Sci 2010552912ndash21

141 Lowenstein O Leyendecker P Lux EA et al

Efficacy and safety of combined prolonged- releaseoxycodone and naloxone in the management ofmoderatesevere chronic non-malignant pain

Results of a prospectively designed pooled analysisof two randomised double-blind clinical trials

BMC Clin Pharmacol 20101012

142 Cryer B Katz S Vallejo R Popescu A Ueno R Arandomized study of lubiprostone for opioid-induced

constipation in patients with chronic noncancerpain Pain Med 2014151825ndash34

143 Freedman MD Schwartz HJ Roby R Fleisher STolerance and efficacy of polyethylene glycol 3350electrolyte solution versus lactulose in relievingopiate induced constipation A double-blindedplacebo-controlled trial J Clin Pharmacol 199737904ndash7

144 Agra Y Sacristan A Gonzalez M et al Efficacy ofsenna versus lactulose in terminal cancer patientstreated with opioids J Pain Symptom Manage1998151ndash7

145 Marciniak CM Toledo S Lee J et al Lubiprostonevs Senna in postoperative orthopedic surgery pa-tients with opioid-induced constipation A double-blind active-comparator trial World JGastroenterol 20142016323ndash33

146 Jamal MM Adams AB Jansen JP Webster LR Arandomized placebo-controlled trial of lubiprostonefor opioid-induced constipation in chronic noncancerpain Am J Gastroenterol 2015110725ndash32

147 Wirz S Nadstawek J Elsen C Junker UWartenberg HC Laxative management in ambula-tory cancer patients on opioid therapy A prospect-ive open-label investigation of polyethylene glycolsodium picosulphate and lactulose Eur J CancerCare 201221131ndash40

148 Ishihara M Ikesue H Matsunaga H A multi-institutional study analyzing effect of prophylacticmedication for prevention of opioid-induced gastro-intestinal dysfunction Clin J Pain 201228373ndash81

149 Pottegard A Knudsen TB van Heesch K et alInformation on risk of constipation for Danish usersof opioids and their laxative use Int J Clin Pharm201436291ndash4

150 Attar A Lemann M Ferguson A et al Comparisonof a low dose polyethylene glycol electrolyte solu-tion with lactulose for treatment of chronic consti-pation Gut 199944226ndash30

151 Basilisco G Marino B Passerini L Ogliari CAbdominal distension after colonic lactulose fer-mentation recorded by a new extensometerNeurogastroenterol Motil 200315427ndash33

152 van der Spoel JI Oudemans-van Straaten HMKuiper MA et al Laxation of critically ill patientswith lactulose or polyethylene glycol A two-centerrandomized double-blind placebo-controlled trialCrit Care Med 2007352726ndash31

153 Bradshaw M Sen A Use of a prophylactic antie-metic with morphine in acute pain Randomisedcontrolled trial Emerg Med J 200623210ndash3

154 Simpson PM Bendall JC Middleton PM Reviewarticle Prophylactic metoclopramide for patientsreceiving intravenous morphine in the emergencysetting A systematic review and meta-analysis ofrandomized controlled trials Emerg Med Australas201123452ndash7

155 Mordarski S Pain management in the elderlyTransdermal fentanyl for the treatment of paincaused by osteoarthritis of the knee and hipBiomed Res Int 20142014262961

156 Hartrick CT Tang YS Hunstad D et al Aprepitantvs multimodal prophylaxis in the prevention of nau-sea and vomiting following extended-release epi-dural morphine Pain Pract 201010245ndash8

157 Bassotti G Blandizzi C Understanding and treat-ing refractory constipation World J GastrointestPharmacol Ther 2014577ndash85

158 Keating GM Prucalopride A review of its use inthe management of chronic constipation Drugs2013731935ndash50

159 Chamberlain SM Rao SS Safety evaluation oflubiprostone in the treatment of constipation and ir-ritable bowel syndrome Expert Opin Drug Saf201211841ndash50

160 Meissner W Leyendecker P Mueller-Lissner Set al A randomised controlled trial with pro-longed-release oral oxycodone and naloxone toprevent and reverse opioid-induced constipationEur J Pain 20091356ndash64

161 De Schepper HU Cremonini F Park MI CamilleriM Opioids and the gut Pharmacology and currentclinical experience Neurogastroenterol Motil 200416383ndash94

162 Webster L Chey WD Tack J et al Randomised clin-ical trial The long-term safety and tolerability of nalox-egol in patients with pain and opioid-inducedconstipation Aliment Pharmacol Ther 201440771ndash9

163 Mackey AC Green L Greene P Avigan MMethylnaltrexone and gastrointestinal perforation JPain Symptom Manage 201040e1ndash3

164 Jagla C Martus P Stein C Peripheral opioid re-ceptor blockade increases postoperative morphinedemandsndasha randomized double-blind placebo-controlled trial Pain 20141552056ndash62

165 Vaughan-Shaw PG Fecher IC Harris S Knight JSA meta-analysis of the effectiveness of the opioidreceptor antagonist alvimopan in reducing hospitallength of stay and time to GI recovery in patients

enrolled in a standardized accelerated recoveryprogram after abdominal surgery Dis ColonRectum 201255611ndash20

166 Kraft MD Emerging pharmacologic options fortreating postoperative ileus Am J Health SystPharm 200764S13ndash20

167 Dunlop W Uhl R Khan I Taylor A Barton GQuality of life benefits and cost impact of pro-longed release oxycodonenaloxone versus pro-

longed release oxycodone in patients withmoderate-to-severe non-malignant pain andopioid-induced constipation A UK cost-utility ana-lysis J Med Econ 201215564ndash75

168 Schutter U Schutter U Grunert S et alInnovative pain therapy with a fixed combinationof prolonged-release oxycodonenaloxone Alarge observational study under conditions ofdaily practice Curr Med Res Opin 2010261377ndash87

APPENDIX

Studies on OIBD were identified with the terms Nauseaor heartburn or regurgitation or fullness or dyspepsia orvomiting or appetite or distension or bloating or abdomi-nal pain or abdominal discomfort or constipation or gas-trointestinal transit or slow transit or delayed transit orcolon transit or defecation or abnormal defecation or dif-ficult defecation or dysmotility or hypomotility or motilitydisorder or motility dysfunction or straining or stool orstool evacuation or incomplete evacuation or hard stoolsor infrequent stools or toilet or bowel function or bowelmovement

These were combined using the set operator AND withstudies identified with the terms Opiate alkaloids or opi-ate analgesics or opiate or opioid or narcotics or mor-phine or oxycodone or fentanyl or tramadol or codeineor hydromorphone or buprenorphine or methadone orhydrocodone or tapentadol or levorphanol or propoxy-phene or tilidine

Studies were further categorized as relating to preva-lence mechanism of OIBD non-pharmacologic treat-ment pharmacologic treatment and opiate antagonistsby combining the results above and five further sets ofsearch terms

To identify studies relating to prevalence the initialresults were combined using the set operator ANDwith the terms Epidemiology or prevalence or frequencyor occurrence or population or cost or burden oreconomic

To identify studies relating to mechanisms of OIBD theinitial results were combined using the set operatorAND with the terms Motility or reflux or esophagealmotility or gastric emptying or colon motility or intestinalmotility or small intestinal motility or secretion or salivarysecretion or intestinal secretion or inhibition or sphincter

To identify studies relating to non-pharmacologic treat-ments the initial results were combined using the setoperator AND with the terms Dietary fiber or ispaghulaor plantago or linseed or flaxseed or flax seed or

wholegrain or dietary fiber or bulking agents or physicalactivity or physiotherapy or exercise or sport or drink orfluid intake or acupuncture or massage or osteopathy

To identify studies relating to pharmacologic treatmentsthe initial results were combined using the set operatorAND with the terms Laxative or macrogol or polyethy-leneglycol or PEG or lactulose or sobitol or bisacodyl orpicosulfate or senna or sennoside or danthron or sero-tonin receptor agonist or 5-HT 4 receptors agonist orguanylate cyclase or chloride channel or prucalopride orlubiprostone or linaclotide or erythromycin orneostigmine

In total the search yielded 10832 unique citations Forinclusion all studies were required to be performed inan adult population who were receiving opioid or opiatedrugs and who had a confirmed diagnosis of OIBDbased on clinical symptoms physicianrsquos opinion orspecific diagnostic criteria specified by study investiga-tors Citations identified within the treatment categorieswere also required to be randomized controlled trialscomparing pharmacologic or non-pharmacologic thera-pies with a control measure There was no minimumduration of therapy but quantitative assessment ofresponse to therapy was required Where trials deemedit necessary results should be supplemented by nega-tive investigations Only publications published in theEnglish language were included in the analysis

Using the above inclusion and exclusion criteria theidentified citations were screened independently by twoinvestigators for relevance by title and then abstract toreduce the citation list to 124 and then 52 citationsrespectively Full publications of the 52 citations wereassessed and following discussion to resolve any dis-agreement a final list of 33 citations was generated[12ndash44]

Voting results table Votes for each statement with anaccompanying level of agreement the strength of theevidence and the strength of the recommendation(when applicable)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

11 The definition of OICOIBD is based on a clinical evaluation

relating to a change in bowel habits during opioid therapy

1000 064

12 The symptoms of OIC are related to the colon whereas

OIBD manifests with symptoms throughout the GI tract

1000 0010

13 Subjective reports of OIC are based on validated question-

naires whereas there is no consensus about assessment of

1000 910

14 Objective assessment of OIBD has focused on motility but

there are only a few human studies on opioid effects on

secretion and sphincter function

1000 460

21 Data on prevalence of OIC differs widely based on the defi-

nitions used and origin of the studies but not on gender

1000 460

22 The type of pure opioid drugs does not influence the preva-

lence of OIC symptoms

1000 0100

23 Dose and frequency of opioids influences likelihood of OIC

symptoms

1000 073

24 Transdermal preparations of fentanyl is associated with

lower incidence of OIC than oral opioids

613 136

25 Duration of opioid therapy influences the impact of OIC

symptoms

1000 0100

31 Opioid receptors are spread throughout the GI tract from

the mid-oesophagus to rectum and are involved in a variety

of cellular functions

1000 1000

32 Opioid agonists administration results in slowing of normal

GI motility segmentation increased tone and uncoordinated

motility reflected in eg increased transit times agreement

1000 460

33 Opioids result in increased absorption and decreased

secretion of fluids in the gut leading to dry feces and less

propulsive motility

1000 055

34 Opioids increase sphincter tone which may cause symp-

toms such as sphincter of Oddi spasms and difficult

defecation

1000 0100

35 Opioid antagonists counteract the effects of opioids in the

human gut on motility fluid transport and sphincter function

1000 0100

41 QoL can be worse due to side effects of opioids 1000 280

42 Assessment of QoL in patients with OICOIBD can assist

therapeutic choices

1000 0100

51 Non-pharmacological treatments of OIC include dietary

recommendations and life-style modifications

1000 0010 010

61 The choice of a laxative to treat OICOIBD depends on the

perceived efficacy and the preference of the patient Indirect

evidence favours bisacodyl sodium picosulfate macrogol

and sennosides as first choice

1000 046 55

62 Sugars and sugar alcohols such as lactulose lactose and

sorbitol should not be used to prevent or treat OIC

1000 091 37

63 Gastro-esophageal reflux symptoms as part of OIBD

should be treated like primary reflux disease

1000 0010 010

64 Patients with nausea secondary to opioid treatment should

be offered dopamine antagonists

910 0010 010

1000 0100 19

(continued)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

65 Treatment of OIC with new laxatives (prucalopride lubipro-

stone) may be promising however to date there are insuffi-

cient data to warrant such treatments in OIC patients

71 Peripherally acting -opioid receptor antagonists

(PAMORAs) effectively reduce OIC

1000 1000 100

72 In patients with chronic cancer or non-cancer pain pro-

longed release naloxoneoxycodone combination effectively

reduces OIC while maintaining equal analgesia to prolonged

release oxycodone alone

1000 1000 100

73 Naloxegol is effective and safe in reducing OIC in patients

with chronic pain

1000 1000 36

74 Methylnaltrexone injections can effectively relieve OIC in

patients with post-operative cancer and non-cancer chronic

pain However concerns regarding reversal of analgesia and

intestinal perforation in relation to its post-operative use have

been raised

1000 1000 100

75 Alvimopan is approved for in-hospital use in the USA for

preventing or shortening the course of postoperative ileus

after bowel resection Long-term safety studies indicated that

it may possibly increase the risk for cardiovascular events

There is some evidence that alvimopan reduces OIC in sub-

jects with chronic opioid intake

1000 1000

76 Both laxatives and opioid antagonists for OIC have benefits

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

GENERAL SECTION

Review Article

Opioid-Induced Constipation and BowelDysfunction A Clinical Guideline

Stefan Muller-Lissner MD Gabrio Bassotti MDdagger

Benoit Coffin MDDagger Asbjoslashrn Mohr Drewes MDsect

Harald Breivik MDpara Elon Eisenberg MDk

Anton Emmanuel MDkj Francoise Laroche MDWinfried Meissner MDdaggerdagger and Bart Morlion MDDaggerDagger

Department of Internal Medicine Park-Klinik

Weissensee Berlin Germanydagger

Gastroenterology and

Hepatology Section Department of Medicine

University of Perugia School of Medicine Piazza

Universita 1 Perugia ItalyDagger

AP-HP Hopital Louis

Mourier University Denis Diderot-Paris 7 INSERM

U987 Paris France sectDepartment of Gastroenterology

and Hepatology Aalborg University Hospital Aalborg

Denmark paraDepartment of Pain Management and

Research University of Oslo Rikshospitalet Oslo

Norway kInstitute of Pain Medicine Rambam Health

Care Campus The Technion Israel Institute of

Technology Haifa Israel kjGI Physiology Unit

University College Hospital Queen Square London

UK Saint-Antoine University Hospital Paris Francedaggerdagger

Jena University Hospital Jena GermanyDaggerDagger

Leuven Center for Algology and Pain Management

University of Leuven KU Leuven Leuven Belgium

Funding sources Funded by an unrestricted educa-

tional grant from Mundipharma International

Disclosures and conflicts of interest Stefan Muller-

Lissner consultancy for Mundipharma International

Develco and Astra Zeneca Gabrio Bassotti consult-

ing fees from Mundipharma International and lecturing

fee from Shire Pharmaceutical for educational pur-

poses Benoit Coffin no conflict of interest Asbjoslashrn

Mohr Drewes no conflict of interest Harald Brevik no

conflict of interest Elon Eisenberg grant from

Mundipharma International to study opioid-induced

hyperalgesia Anton Emmanuel advisory board for

NAPP Shire and Takeda Francoise Laroche consult-

ancy for Mylan Grunenthal and Mundipharma

International Winfried Meissner advisory boards for

Menarini Grunenthal BioQPharma Medicines

Company and Mundipharma International No com-

peting interests

Correspondence to Stefan Muller-Lissner MD

Eisenacherstrasse 103D 10781 Berlin Germany Tel

thorn49 30 21997504 Mobile thorn49 151 12629359 Fax

thorn49 96 283605 E-mail stefanmueller-Lissnerde

Abstract

Objective To formulate timely evidence-basedguidelines for the management of opioid-inducedbowel dysfunction

Setting Constipation is a major untoward effect ofopioids Increasing prescription of opioids has cor-related to increased incidence of opioid-inducedconstipation However the inhibitory effects of opi-oids are not confined to the colon but also affecthigher segments of the gastrointestinal tract lead-ing to the coining of the term ldquoopioid-inducedbowel dysfunctionrdquo

Methods A literature search was conducted usingMedline EMBASE and EMBASE Classic and theCochrane Central Register of Controlled TrialsPredefined search terms and inclusionexclusioncriteria were used to identify and categorize rele-vant papers A series of statements were formulatedand justified by a comment then labeled with thedegree of agreement and their level of evidence asjudged by the Strength of RecommendationTaxonomy (SORT) system

Results From a list of 10832 potentially relevantstudies 33 citations were identified for reviewScreening the reference lists of the pertinent papersidentified additional publications Current defin-itions prevalence and mechanism of opioid-induced bowel dysfunction were reviewed and atreatment algorithm and statements regarding pa-tient management were developed to provide

VC 2016 American Academy of Pain Medicine

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (httpcreativecommonsorg

licensesby-nc40) which permits non-commercial re-use distribution and reproduction in any medium provided the original work is properly cited

For commercial re-use please contact journalspermissionsoupcom 1837

Pain Medicine 2017 18 1837ndash1863doi 101093pmpnw255

Introduction

Methods

Function

Prevalence

Mechanisms of OIBD

Modifications

aldesig

rvention

variable

Results

Random

double

cebo-c

tenance

self-d

efined

constipation

col3350e

Baselin

Random

inally

patients

self-d

efined

12ndash48

15ndash60

cation-f

rval72-h

period

xative

Random

cebo-c

double

hopedic

patients

self-p

1additio

(ldquo2

capsule

srdquo)

Change

2(Pfrac14

Random

ddouble

noncancer

patients

additio

nalsym

ecrite

Change

Random

cebo-c

double

noncancer

patients

1additio

ecrite

Responder

(Pfrac14

al2015

(continued)

aldesig

rvention

variable

Results

Random

double

noncancer

patients

ldquocle

patients

baselin

Results

BIDfrac14

edaily

ICfrac14

id-induce

dconstipation

Mfrac14

sponta

induced

additi

onalla

xative

Mfrac14

aldesig

rvention

Results

Random

ddouble

epatients

noncancer

ldquowith

equency

idusage

xone-t

patients

frequency

patient

3patients

experienced

rsalof

random

lleltr

patients

noncancer

ldquowith

longed-r

oxycodonen

longed-r

oxycodonep

lacebo

random

findin

cebo-c

lleltr

patients

cancer

ldquowith

concom

constipationrdquo

oxycodone

ependent

random

cebo-c

lleltr

patients

noncancer

longed-r

oxycodone

60ndash80

longed-r

oxycodonep

lacebo

reduced

in2009

random

cebo-c

lleltr

patients

modera

cancer

longed-r

oxycodone)

longed-r

oxycodonep

lacebo

laxative

innalo

edzai2012

[3353]

Ifrac14B

Function

OICfrac14

dconstipation

Mfrac14

sponta

induce

additi

laxative

Mfrac14

TIDfrac14

xegolfo

rvention

Results

random

dose-f

cebo-c

llelgro

patients

cancer-

xegol(5

nchange

baselin

(Pfrac14

Webste

enticalphase

random

double

llelgro

atients

noncancer

response

final4

weeks)

(Pfrac14

inboth

random

llelgro

patients

noncancer

xegol25

0ndash10

eequiv

Long-t

rabili

occurr

frequently

inalpain

nausea

headache

Webste

AEfrac14

Mfrac14

sponta

induced

additi

onalla

xative

OCfrac14

ylnaltr

aldesig

rvention

variable

Results

tochro

respective

Laxation

response

-coecal

transit

patients

treate

xation

response

-coecaltr

random

cebo-c

double

patients

illness

within

4hours

treatm

Laxation

within

4hours

respective

Random

double

cebo-c

patients

illness

laxative

treatm

initia

4hours

response

respective

ly(Pfrac14

patients

report

laxative

Random

cebo-c

patients

noncancer

ctions

leadin

within

4hours

within

4hours

(daily

altern

respective

(continued)

aldesig

rvention

variable

Results

random

double

llel-gro

cebo-c

patients

hopedic

cedure

likely

ization

Once-d

laxation

patients

experiencin

laxation

within

4hours

Laxation

within

2hours

(Pfrac14

4hours

(Pfrac14

laxation

(Pfrac14

OICfrac14

id-induce

dconstipation

Mfrac14

sponta

induced

additi

onalla

xative

Cfrac14

subcuta

aldesig

rvention

variable

Results

Random

cebo-c

double

patients

(Nfrac14

iddependence

(Nfrac14

imopan

patients

within

8hours

patients

8hours

imopan

respective

random

cebo-c

double

noncancer

imopan

Change

imopan

(thorn17

imopan

ID(thorn

imopan

ID(thorn

Webste

random

cebo-c

double

patients

noncancer

imopan

patients

inbaselin

imopan

Jansen

Random

cebo-c

double

patients

noncancer

imopan

patients

sponders

inboth

imopan

tistically

BIDfrac14

edaily

ICfrac14

id-induce

dconstipation

QIDfrac14

Mfrac14

sponta

induce

additi

onalla

xative

Disease

Antagonists

Acknowledgments

182S11ndash8

20002019ndash26

611181ndash7

71425ndash33

10397ndash401

97129ndash34

Sci 2014132557ndash68

1997113409ndash14

292G377ndash84

20453ndash8

47230ndash6

144218ndash38

APPENDIX

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 064

1000 0010

1000 910

1000 460

1000 0100

symptoms

1000 073

613 136

symptoms

1000 0100

1000 1000

1000 460

propulsive motility

1000 055

defecation

1000 0100

therapeutic choices

1000 0100

1000 0010 010

1000 046 55

1000 091 37

1000 0010 010

910 0010 010

1000 0100 19

(continued)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 1000 100

with chronic pain

1000 1000 36

been raised

1000 1000 100

1000 1000

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

Introduction

Methods

Function

Prevalence

Mechanisms of OIBD

Modifications

aldesig

rvention

variable

Results

Random

double

cebo-c

tenance

self-d

efined

constipation

col3350e

Baselin

Random

inally

patients

self-d

efined

12ndash48

15ndash60

cation-f

rval72-h

period

xative

Random

cebo-c

double

hopedic

patients

self-p

1additio

(ldquo2

capsule

srdquo)

Change

2(Pfrac14

Random

ddouble

noncancer

patients

additio

nalsym

ecrite

Change

Random

cebo-c

double

noncancer

patients

1additio

ecrite

Responder

(Pfrac14

al2015

(continued)

aldesig

rvention

variable

Results

Random

double

noncancer

patients

ldquocle

patients

baselin

Results

BIDfrac14

edaily

ICfrac14

id-induce

dconstipation

Mfrac14

sponta

induced

additi

onalla

xative

Mfrac14

aldesig

rvention

Results

Random

ddouble

epatients

noncancer

ldquowith

equency

idusage

xone-t

patients

frequency

patient

3patients

experienced

rsalof

random

lleltr

patients

noncancer

ldquowith

longed-r

oxycodonen

longed-r

oxycodonep

lacebo

random

findin

cebo-c

lleltr

patients

cancer

ldquowith

concom

constipationrdquo

oxycodone

ependent

random

cebo-c

lleltr

patients

noncancer

longed-r

oxycodone

60ndash80

longed-r

oxycodonep

lacebo

reduced

in2009

random

cebo-c

lleltr

patients

modera

cancer

longed-r

oxycodone)

longed-r

oxycodonep

lacebo

laxative

innalo

edzai2012

[3353]

Ifrac14B

Function

OICfrac14

dconstipation

Mfrac14

sponta

induce

additi

laxative

Mfrac14

TIDfrac14

xegolfo

rvention

Results

random

dose-f

cebo-c

llelgro

patients

cancer-

xegol(5

nchange

baselin

(Pfrac14

Webste

enticalphase

random

double

llelgro

atients

noncancer

response

final4

weeks)

(Pfrac14

inboth

random

llelgro

patients

noncancer

xegol25

0ndash10

eequiv

Long-t

rabili

occurr

frequently

inalpain

nausea

headache

Webste

AEfrac14

Mfrac14

sponta

induced

additi

onalla

xative

OCfrac14

ylnaltr

aldesig

rvention

variable

Results

tochro

respective

Laxation

response

-coecal

transit

patients

treate

xation

response

-coecaltr

random

cebo-c

double

patients

illness

within

4hours

treatm

Laxation

within

4hours

respective

Random

double

cebo-c

patients

illness

laxative

treatm

initia

4hours

response

respective

ly(Pfrac14

patients

report

laxative

Random

cebo-c

patients

noncancer

ctions

leadin

within

4hours

within

4hours

(daily

altern

respective

(continued)

aldesig

rvention

variable

Results

random

double

llel-gro

cebo-c

patients

hopedic

cedure

likely

ization

Once-d

laxation

patients

experiencin

laxation

within

4hours

Laxation

within

2hours

(Pfrac14

4hours

(Pfrac14

laxation

(Pfrac14

OICfrac14

id-induce

dconstipation

Mfrac14

sponta

induced

additi

onalla

xative

Cfrac14

subcuta

aldesig

rvention

variable

Results

Random

cebo-c

double

patients

(Nfrac14

iddependence

(Nfrac14

imopan

patients

within

8hours

patients

8hours

imopan

respective

random

cebo-c

double

noncancer

imopan

Change

imopan

(thorn17

imopan

ID(thorn

imopan

ID(thorn

Webste

random

cebo-c

double

patients

noncancer

imopan

patients

inbaselin

imopan

Jansen

Random

cebo-c

double

patients

noncancer

imopan

patients

sponders

inboth

imopan

tistically

BIDfrac14

edaily

ICfrac14

id-induce

dconstipation

QIDfrac14

Mfrac14

sponta

induce

additi

onalla

xative

Disease

Antagonists

Acknowledgments

182S11ndash8

20002019ndash26

611181ndash7

71425ndash33

10397ndash401

97129ndash34

Sci 2014132557ndash68

1997113409ndash14

292G377ndash84

20453ndash8

47230ndash6

144218ndash38

APPENDIX

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 064

1000 0010

1000 910

1000 460

1000 0100

symptoms

1000 073

613 136

symptoms

1000 0100

1000 1000

1000 460

propulsive motility

1000 055

defecation

1000 0100

therapeutic choices

1000 0100

1000 0010 010

1000 046 55

1000 091 37

1000 0010 010

910 0010 010

1000 0100 19

(continued)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 1000 100

with chronic pain

1000 1000 36

been raised

1000 1000 100

1000 1000

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

Function

Prevalence

Mechanisms of OIBD

Modifications

aldesig

rvention

variable

Results

Random

double

cebo-c

tenance

self-d

efined

constipation

col3350e

Baselin

Random

inally

patients

self-d

efined

12ndash48

15ndash60

cation-f

rval72-h

period

xative

Random

cebo-c

double

hopedic

patients

self-p

1additio

(ldquo2

capsule

srdquo)

Change

2(Pfrac14

Random

ddouble

noncancer

patients

additio

nalsym

ecrite

Change

Random

cebo-c

double

noncancer

patients

1additio

ecrite

Responder

(Pfrac14

al2015

(continued)

aldesig

rvention

variable

Results

Random

double

noncancer

patients

ldquocle

patients

baselin

Results

BIDfrac14

edaily

ICfrac14

id-induce

dconstipation

Mfrac14

sponta

induced

additi

onalla

xative

Mfrac14

aldesig

rvention

Results

Random

ddouble

epatients

noncancer

ldquowith

equency

idusage

xone-t

patients

frequency

patient

3patients

experienced

rsalof

random

lleltr

patients

noncancer

ldquowith

longed-r

oxycodonen

longed-r

oxycodonep

lacebo

random

findin

cebo-c

lleltr

patients

cancer

ldquowith

concom

constipationrdquo

oxycodone

ependent

random

cebo-c

lleltr

patients

noncancer

longed-r

oxycodone

60ndash80

longed-r

oxycodonep

lacebo

reduced

in2009

random

cebo-c

lleltr

patients

modera

cancer

longed-r

oxycodone)

longed-r

oxycodonep

lacebo

laxative

innalo

edzai2012

[3353]

Ifrac14B

Function

OICfrac14

dconstipation

Mfrac14

sponta

induce

additi

laxative

Mfrac14

TIDfrac14

xegolfo

rvention

Results

random

dose-f

cebo-c

llelgro

patients

cancer-

xegol(5

nchange

baselin

(Pfrac14

Webste

enticalphase

random

double

llelgro

atients

noncancer

response

final4

weeks)

(Pfrac14

inboth

random

llelgro

patients

noncancer

xegol25

0ndash10

eequiv

Long-t

rabili

occurr

frequently

inalpain

nausea

headache

Webste

AEfrac14

Mfrac14

sponta

induced

additi

onalla

xative

OCfrac14

ylnaltr

aldesig

rvention

variable

Results

tochro

respective

Laxation

response

-coecal

transit

patients

treate

xation

response

-coecaltr

random

cebo-c

double

patients

illness

within

4hours

treatm

Laxation

within

4hours

respective

Random

double

cebo-c

patients

illness

laxative

treatm

initia

4hours

response

respective

ly(Pfrac14

patients

report

laxative

Random

cebo-c

patients

noncancer

ctions

leadin

within

4hours

within

4hours

(daily

altern

respective

(continued)

aldesig

rvention

variable

Results

random

double

llel-gro

cebo-c

patients

hopedic

cedure

likely

ization

Once-d

laxation

patients

experiencin

laxation

within

4hours

Laxation

within

2hours

(Pfrac14

4hours

(Pfrac14

laxation

(Pfrac14

OICfrac14

id-induce

dconstipation

Mfrac14

sponta

induced

additi

onalla

xative

Cfrac14

subcuta

aldesig

rvention

variable

Results

Random

cebo-c

double

patients

(Nfrac14

iddependence

(Nfrac14

imopan

patients

within

8hours

patients

8hours

imopan

respective

random

cebo-c

double

noncancer

imopan

Change

imopan

(thorn17

imopan

ID(thorn

imopan

ID(thorn

Webste

random

cebo-c

double

patients

noncancer

imopan

patients

inbaselin

imopan

Jansen

Random

cebo-c

double

patients

noncancer

imopan

patients

sponders

inboth

imopan

tistically

BIDfrac14

edaily

ICfrac14

id-induce

dconstipation

QIDfrac14

Mfrac14

sponta

induce

additi

onalla

xative

Disease

Antagonists

Acknowledgments

182S11ndash8

20002019ndash26

611181ndash7

71425ndash33

10397ndash401

97129ndash34

Sci 2014132557ndash68

1997113409ndash14

292G377ndash84

20453ndash8

47230ndash6

144218ndash38

APPENDIX

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 064

1000 0010

1000 910

1000 460

1000 0100

symptoms

1000 073

613 136

symptoms

1000 0100

1000 1000

1000 460

propulsive motility

1000 055

defecation

1000 0100

therapeutic choices

1000 0100

1000 0010 010

1000 046 55

1000 091 37

1000 0010 010

910 0010 010

1000 0100 19

(continued)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 1000 100

with chronic pain

1000 1000 36

been raised

1000 1000 100

1000 1000

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

Function

Prevalence

Mechanisms of OIBD

Modifications

aldesig

rvention

variable

Results

Random

double

cebo-c

tenance

self-d

efined

constipation

col3350e

Baselin

Random

inally

patients

self-d

efined

12ndash48

15ndash60

cation-f

rval72-h

period

xative

Random

cebo-c

double

hopedic

patients

self-p

1additio

(ldquo2

capsule

srdquo)

Change

2(Pfrac14

Random

ddouble

noncancer

patients

additio

nalsym

ecrite

Change

Random

cebo-c

double

noncancer

patients

1additio

ecrite

Responder

(Pfrac14

al2015

(continued)

aldesig

rvention

variable

Results

Random

double

noncancer

patients

ldquocle

patients

baselin

Results

BIDfrac14

edaily

ICfrac14

id-induce

dconstipation

Mfrac14

sponta

induced

additi

onalla

xative

Mfrac14

aldesig

rvention

Results

Random

ddouble

epatients

noncancer

ldquowith

equency

idusage

xone-t

patients

frequency

patient

3patients

experienced

rsalof

random

lleltr

patients

noncancer

ldquowith

longed-r

oxycodonen

longed-r

oxycodonep

lacebo

random

findin

cebo-c

lleltr

patients

cancer

ldquowith

concom

constipationrdquo

oxycodone

ependent

random

cebo-c

lleltr

patients

noncancer

longed-r

oxycodone

60ndash80

longed-r

oxycodonep

lacebo

reduced

in2009

random

cebo-c

lleltr

patients

modera

cancer

longed-r

oxycodone)

longed-r

oxycodonep

lacebo

laxative

innalo

edzai2012

[3353]

Ifrac14B

Function

OICfrac14

dconstipation

Mfrac14

sponta

induce

additi

laxative

Mfrac14

TIDfrac14

xegolfo

rvention

Results

random

dose-f

cebo-c

llelgro

patients

cancer-

xegol(5

nchange

baselin

(Pfrac14

Webste

enticalphase

random

double

llelgro

atients

noncancer

response

final4

weeks)

(Pfrac14

inboth

random

llelgro

patients

noncancer

xegol25

0ndash10

eequiv

Long-t

rabili

occurr

frequently

inalpain

nausea

headache

Webste

AEfrac14

Mfrac14

sponta

induced

additi

onalla

xative

OCfrac14

ylnaltr

aldesig

rvention

variable

Results

tochro

respective

Laxation

response

-coecal

transit

patients

treate

xation

response

-coecaltr

random

cebo-c

double

patients

illness

within

4hours

treatm

Laxation

within

4hours

respective

Random

double

cebo-c

patients

illness

laxative

treatm

initia

4hours

response

respective

ly(Pfrac14

patients

report

laxative

Random

cebo-c

patients

noncancer

ctions

leadin

within

4hours

within

4hours

(daily

altern

respective

(continued)

aldesig

rvention

variable

Results

random

double

llel-gro

cebo-c

patients

hopedic

cedure

likely

ization

Once-d

laxation

patients

experiencin

laxation

within

4hours

Laxation

within

2hours

(Pfrac14

4hours

(Pfrac14

laxation

(Pfrac14

OICfrac14

id-induce

dconstipation

Mfrac14

sponta

induced

additi

onalla

xative

Cfrac14

subcuta

aldesig

rvention

variable

Results

Random

cebo-c

double

patients

(Nfrac14

iddependence

(Nfrac14

imopan

patients

within

8hours

patients

8hours

imopan

respective

random

cebo-c

double

noncancer

imopan

Change

imopan

(thorn17

imopan

ID(thorn

imopan

ID(thorn

Webste

random

cebo-c

double

patients

noncancer

imopan

patients

inbaselin

imopan

Jansen

Random

cebo-c

double

patients

noncancer

imopan

patients

sponders

inboth

imopan

tistically

BIDfrac14

edaily

ICfrac14

id-induce

dconstipation

QIDfrac14

Mfrac14

sponta

induce

additi

onalla

xative

Disease

Antagonists

Acknowledgments

182S11ndash8

20002019ndash26

611181ndash7

71425ndash33

10397ndash401

97129ndash34

Sci 2014132557ndash68

1997113409ndash14

292G377ndash84

20453ndash8

47230ndash6

144218ndash38

APPENDIX

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 064

1000 0010

1000 910

1000 460

1000 0100

symptoms

1000 073

613 136

symptoms

1000 0100

1000 1000

1000 460

propulsive motility

1000 055

defecation

1000 0100

therapeutic choices

1000 0100

1000 0010 010

1000 046 55

1000 091 37

1000 0010 010

910 0010 010

1000 0100 19

(continued)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 1000 100

with chronic pain

1000 1000 36

been raised

1000 1000 100

1000 1000

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

Mechanisms of OIBD

Modifications

aldesig

rvention

variable

Results

Random

double

cebo-c

tenance

self-d

efined

constipation

col3350e

Baselin

Random

inally

patients

self-d

efined

12ndash48

15ndash60

cation-f

rval72-h

period

xative

Random

cebo-c

double

hopedic

patients

self-p

1additio

(ldquo2

capsule

srdquo)

Change

2(Pfrac14

Random

ddouble

noncancer

patients

additio

nalsym

ecrite

Change

Random

cebo-c

double

noncancer

patients

1additio

ecrite

Responder

(Pfrac14

al2015

(continued)

aldesig

rvention

variable

Results

Random

double

noncancer

patients

ldquocle

patients

baselin

Results

BIDfrac14

edaily

ICfrac14

id-induce

dconstipation

Mfrac14

sponta

induced

additi

onalla

xative

Mfrac14

aldesig

rvention

Results

Random

ddouble

epatients

noncancer

ldquowith

equency

idusage

xone-t

patients

frequency

patient

3patients

experienced

rsalof

random

lleltr

patients

noncancer

ldquowith

longed-r

oxycodonen

longed-r

oxycodonep

lacebo

random

findin

cebo-c

lleltr

patients

cancer

ldquowith

concom

constipationrdquo

oxycodone

ependent

random

cebo-c

lleltr

patients

noncancer

longed-r

oxycodone

60ndash80

longed-r

oxycodonep

lacebo

reduced

in2009

random

cebo-c

lleltr

patients

modera

cancer

longed-r

oxycodone)

longed-r

oxycodonep

lacebo

laxative

innalo

edzai2012

[3353]

Ifrac14B

Function

OICfrac14

dconstipation

Mfrac14

sponta

induce

additi

laxative

Mfrac14

TIDfrac14

xegolfo

rvention

Results

random

dose-f

cebo-c

llelgro

patients

cancer-

xegol(5

nchange

baselin

(Pfrac14

Webste

enticalphase

random

double

llelgro

atients

noncancer

response

final4

weeks)

(Pfrac14

inboth

random

llelgro

patients

noncancer

xegol25

0ndash10

eequiv

Long-t

rabili

occurr

frequently

inalpain

nausea

headache

Webste

AEfrac14

Mfrac14

sponta

induced

additi

onalla

xative

OCfrac14

ylnaltr

aldesig

rvention

variable

Results

tochro

respective

Laxation

response

-coecal

transit

patients

treate

xation

response

-coecaltr

random

cebo-c

double

patients

illness

within

4hours

treatm

Laxation

within

4hours

respective

Random

double

cebo-c

patients

illness

laxative

treatm

initia

4hours

response

respective

ly(Pfrac14

patients

report

laxative

Random

cebo-c

patients

noncancer

ctions

leadin

within

4hours

within

4hours

(daily

altern

respective

(continued)

aldesig

rvention

variable

Results

random

double

llel-gro

cebo-c

patients

hopedic

cedure

likely

ization

Once-d

laxation

patients

experiencin

laxation

within

4hours

Laxation

within

2hours

(Pfrac14

4hours

(Pfrac14

laxation

(Pfrac14

OICfrac14

id-induce

dconstipation

Mfrac14

sponta

induced

additi

onalla

xative

Cfrac14

subcuta

aldesig

rvention

variable

Results

Random

cebo-c

double

patients

(Nfrac14

iddependence

(Nfrac14

imopan

patients

within

8hours

patients

8hours

imopan

respective

random

cebo-c

double

noncancer

imopan

Change

imopan

(thorn17

imopan

ID(thorn

imopan

ID(thorn

Webste

random

cebo-c

double

patients

noncancer

imopan

patients

inbaselin

imopan

Jansen

Random

cebo-c

double

patients

noncancer

imopan

patients

sponders

inboth

imopan

tistically

BIDfrac14

edaily

ICfrac14

id-induce

dconstipation

QIDfrac14

Mfrac14

sponta

induce

additi

onalla

xative

Disease

Antagonists

Acknowledgments

182S11ndash8

20002019ndash26

611181ndash7

71425ndash33

10397ndash401

97129ndash34

Sci 2014132557ndash68

1997113409ndash14

292G377ndash84

20453ndash8

47230ndash6

144218ndash38

APPENDIX

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 064

1000 0010

1000 910

1000 460

1000 0100

symptoms

1000 073

613 136

symptoms

1000 0100

1000 1000

1000 460

propulsive motility

1000 055

defecation

1000 0100

therapeutic choices

1000 0100

1000 0010 010

1000 046 55

1000 091 37

1000 0010 010

910 0010 010

1000 0100 19

(continued)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 1000 100

with chronic pain

1000 1000 36

been raised

1000 1000 100

1000 1000

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

Modifications

aldesig

rvention

variable

Results

Random

double

cebo-c

tenance

self-d

efined

constipation

col3350e

Baselin

Random

inally

patients

self-d

efined

12ndash48

15ndash60

cation-f

rval72-h

period

xative

Random

cebo-c

double

hopedic

patients

self-p

1additio

(ldquo2

capsule

srdquo)

Change

2(Pfrac14

Random

ddouble

noncancer

patients

additio

nalsym

ecrite

Change

Random

cebo-c

double

noncancer

patients

1additio

ecrite

Responder

(Pfrac14

al2015

(continued)

aldesig

rvention

variable

Results

Random

double

noncancer

patients

ldquocle

patients

baselin

Results

BIDfrac14

edaily

ICfrac14

id-induce

dconstipation

Mfrac14

sponta

induced

additi

onalla

xative

Mfrac14

aldesig

rvention

Results

Random

ddouble

epatients

noncancer

ldquowith

equency

idusage

xone-t

patients

frequency

patient

3patients

experienced

rsalof

random

lleltr

patients

noncancer

ldquowith

longed-r

oxycodonen

longed-r

oxycodonep

lacebo

random

findin

cebo-c

lleltr

patients

cancer

ldquowith

concom

constipationrdquo

oxycodone

ependent

random

cebo-c

lleltr

patients

noncancer

longed-r

oxycodone

60ndash80

longed-r

oxycodonep

lacebo

reduced

in2009

random

cebo-c

lleltr

patients

modera

cancer

longed-r

oxycodone)

longed-r

oxycodonep

lacebo

laxative

innalo

edzai2012

[3353]

Ifrac14B

Function

OICfrac14

dconstipation

Mfrac14

sponta

induce

additi

laxative

Mfrac14

TIDfrac14

xegolfo

rvention

Results

random

dose-f

cebo-c

llelgro

patients

cancer-

xegol(5

nchange

baselin

(Pfrac14

Webste

enticalphase

random

double

llelgro

atients

noncancer

response

final4

weeks)

(Pfrac14

inboth

random

llelgro

patients

noncancer

xegol25

0ndash10

eequiv

Long-t

rabili

occurr

frequently

inalpain

nausea

headache

Webste

AEfrac14

Mfrac14

sponta

induced

additi

onalla

xative

OCfrac14

ylnaltr

aldesig

rvention

variable

Results

tochro

respective

Laxation

response

-coecal

transit

patients

treate

xation

response

-coecaltr

random

cebo-c

double

patients

illness

within

4hours

treatm

Laxation

within

4hours

respective

Random

double

cebo-c

patients

illness

laxative

treatm

initia

4hours

response

respective

ly(Pfrac14

patients

report

laxative

Random

cebo-c

patients

noncancer

ctions

leadin

within

4hours

within

4hours

(daily

altern

respective

(continued)

aldesig

rvention

variable

Results

random

double

llel-gro

cebo-c

patients

hopedic

cedure

likely

ization

Once-d

laxation

patients

experiencin

laxation

within

4hours

Laxation

within

2hours

(Pfrac14

4hours

(Pfrac14

laxation

(Pfrac14

OICfrac14

id-induce

dconstipation

Mfrac14

sponta

induced

additi

onalla

xative

Cfrac14

subcuta

aldesig

rvention

variable

Results

Random

cebo-c

double

patients

(Nfrac14

iddependence

(Nfrac14

imopan

patients

within

8hours

patients

8hours

imopan

respective

random

cebo-c

double

noncancer

imopan

Change

imopan

(thorn17

imopan

ID(thorn

imopan

ID(thorn

Webste

random

cebo-c

double

patients

noncancer

imopan

patients

inbaselin

imopan

Jansen

Random

cebo-c

double

patients

noncancer

imopan

patients

sponders

inboth

imopan

tistically

BIDfrac14

edaily

ICfrac14

id-induce

dconstipation

QIDfrac14

Mfrac14

sponta

induce

additi

onalla

xative

Disease

Antagonists

Acknowledgments

182S11ndash8

20002019ndash26

611181ndash7

71425ndash33

10397ndash401

97129ndash34

Sci 2014132557ndash68

1997113409ndash14

292G377ndash84

20453ndash8

47230ndash6

144218ndash38

APPENDIX

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 064

1000 0010

1000 910

1000 460

1000 0100

symptoms

1000 073

613 136

symptoms

1000 0100

1000 1000

1000 460

propulsive motility

1000 055

defecation

1000 0100

therapeutic choices

1000 0100

1000 0010 010

1000 046 55

1000 091 37

1000 0010 010

910 0010 010

1000 0100 19

(continued)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 1000 100

with chronic pain

1000 1000 36

been raised

1000 1000 100

1000 1000

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

Modifications

aldesig

rvention

variable

Results

Random

double

cebo-c

tenance

self-d

efined

constipation

col3350e

Baselin

Random

inally

patients

self-d

efined

12ndash48

15ndash60

cation-f

rval72-h

period

xative

Random

cebo-c

double

hopedic

patients

self-p

1additio

(ldquo2

capsule

srdquo)

Change

2(Pfrac14

Random

ddouble

noncancer

patients

additio

nalsym

ecrite

Change

Random

cebo-c

double

noncancer

patients

1additio

ecrite

Responder

(Pfrac14

al2015

(continued)

aldesig

rvention

variable

Results

Random

double

noncancer

patients

ldquocle

patients

baselin

Results

BIDfrac14

edaily

ICfrac14

id-induce

dconstipation

Mfrac14

sponta

induced

additi

onalla

xative

Mfrac14

aldesig

rvention

Results

Random

ddouble

epatients

noncancer

ldquowith

equency

idusage

xone-t

patients

frequency

patient

3patients

experienced

rsalof

random

lleltr

patients

noncancer

ldquowith

longed-r

oxycodonen

longed-r

oxycodonep

lacebo

random

findin

cebo-c

lleltr

patients

cancer

ldquowith

concom

constipationrdquo

oxycodone

ependent

random

cebo-c

lleltr

patients

noncancer

longed-r

oxycodone

60ndash80

longed-r

oxycodonep

lacebo

reduced

in2009

random

cebo-c

lleltr

patients

modera

cancer

longed-r

oxycodone)

longed-r

oxycodonep

lacebo

laxative

innalo

edzai2012

[3353]

Ifrac14B

Function

OICfrac14

dconstipation

Mfrac14

sponta

induce

additi

laxative

Mfrac14

TIDfrac14

xegolfo

rvention

Results

random

dose-f

cebo-c

llelgro

patients

cancer-

xegol(5

nchange

baselin

(Pfrac14

Webste

enticalphase

random

double

llelgro

atients

noncancer

response

final4

weeks)

(Pfrac14

inboth

random

llelgro

patients

noncancer

xegol25

0ndash10

eequiv

Long-t

rabili

occurr

frequently

inalpain

nausea

headache

Webste

AEfrac14

Mfrac14

sponta

induced

additi

onalla

xative

OCfrac14

ylnaltr

aldesig

rvention

variable

Results

tochro

respective

Laxation

response

-coecal

transit

patients

treate

xation

response

-coecaltr

random

cebo-c

double

patients

illness

within

4hours

treatm

Laxation

within

4hours

respective

Random

double

cebo-c

patients

illness

laxative

treatm

initia

4hours

response

respective

ly(Pfrac14

patients

report

laxative

Random

cebo-c

patients

noncancer

ctions

leadin

within

4hours

within

4hours

(daily

altern

respective

(continued)

aldesig

rvention

variable

Results

random

double

llel-gro

cebo-c

patients

hopedic

cedure

likely

ization

Once-d

laxation

patients

experiencin

laxation

within

4hours

Laxation

within

2hours

(Pfrac14

4hours

(Pfrac14

laxation

(Pfrac14

OICfrac14

id-induce

dconstipation

Mfrac14

sponta

induced

additi

onalla

xative

Cfrac14

subcuta

aldesig

rvention

variable

Results

Random

cebo-c

double

patients

(Nfrac14

iddependence

(Nfrac14

imopan

patients

within

8hours

patients

8hours

imopan

respective

random

cebo-c

double

noncancer

imopan

Change

imopan

(thorn17

imopan

ID(thorn

imopan

ID(thorn

Webste

random

cebo-c

double

patients

noncancer

imopan

patients

inbaselin

imopan

Jansen

Random

cebo-c

double

patients

noncancer

imopan

patients

sponders

inboth

imopan

tistically

BIDfrac14

edaily

ICfrac14

id-induce

dconstipation

QIDfrac14

Mfrac14

sponta

induce

additi

onalla

xative

Disease

Antagonists

Acknowledgments

182S11ndash8

20002019ndash26

611181ndash7

71425ndash33

10397ndash401

97129ndash34

Sci 2014132557ndash68

1997113409ndash14

292G377ndash84

20453ndash8

47230ndash6

144218ndash38

APPENDIX

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 064

1000 0010

1000 910

1000 460

1000 0100

symptoms

1000 073

613 136

symptoms

1000 0100

1000 1000

1000 460

propulsive motility

1000 055

defecation

1000 0100

therapeutic choices

1000 0100

1000 0010 010

1000 046 55

1000 091 37

1000 0010 010

910 0010 010

1000 0100 19

(continued)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 1000 100

with chronic pain

1000 1000 36

been raised

1000 1000 100

1000 1000

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

aldesig

rvention

variable

Results

Random

double

cebo-c

tenance

self-d

efined

constipation

col3350e

Baselin

Random

inally

patients

self-d

efined

12ndash48

15ndash60

cation-f

rval72-h

period

xative

Random

cebo-c

double

hopedic

patients

self-p

1additio

(ldquo2

capsule

srdquo)

Change

2(Pfrac14

Random

ddouble

noncancer

patients

additio

nalsym

ecrite

Change

Random

cebo-c

double

noncancer

patients

1additio

ecrite

Responder

(Pfrac14

al2015

(continued)

aldesig

rvention

variable

Results

Random

double

noncancer

patients

ldquocle

patients

baselin

Results

BIDfrac14

edaily

ICfrac14

id-induce

dconstipation

Mfrac14

sponta

induced

additi

onalla

xative

Mfrac14

aldesig

rvention

Results

Random

ddouble

epatients

noncancer

ldquowith

equency

idusage

xone-t

patients

frequency

patient

3patients

experienced

rsalof

random

lleltr

patients

noncancer

ldquowith

longed-r

oxycodonen

longed-r

oxycodonep

lacebo

random

findin

cebo-c

lleltr

patients

cancer

ldquowith

concom

constipationrdquo

oxycodone

ependent

random

cebo-c

lleltr

patients

noncancer

longed-r

oxycodone

60ndash80

longed-r

oxycodonep

lacebo

reduced

in2009

random

cebo-c

lleltr

patients

modera

cancer

longed-r

oxycodone)

longed-r

oxycodonep

lacebo

laxative

innalo

edzai2012

[3353]

Ifrac14B

Function

OICfrac14

dconstipation

Mfrac14

sponta

induce

additi

laxative

Mfrac14

TIDfrac14

xegolfo

rvention

Results

random

dose-f

cebo-c

llelgro

patients

cancer-

xegol(5

nchange

baselin

(Pfrac14

Webste

enticalphase

random

double

llelgro

atients

noncancer

response

final4

weeks)

(Pfrac14

inboth

random

llelgro

patients

noncancer

xegol25

0ndash10

eequiv

Long-t

rabili

occurr

frequently

inalpain

nausea

headache

Webste

AEfrac14

Mfrac14

sponta

induced

additi

onalla

xative

OCfrac14

ylnaltr

aldesig

rvention

variable

Results

tochro

respective

Laxation

response

-coecal

transit

patients

treate

xation

response

-coecaltr

random

cebo-c

double

patients

illness

within

4hours

treatm

Laxation

within

4hours

respective

Random

double

cebo-c

patients

illness

laxative

treatm

initia

4hours

response

respective

ly(Pfrac14

patients

report

laxative

Random

cebo-c

patients

noncancer

ctions

leadin

within

4hours

within

4hours

(daily

altern

respective

(continued)

aldesig

rvention

variable

Results

random

double

llel-gro

cebo-c

patients

hopedic

cedure

likely

ization

Once-d

laxation

patients

experiencin

laxation

within

4hours

Laxation

within

2hours

(Pfrac14

4hours

(Pfrac14

laxation

(Pfrac14

OICfrac14

id-induce

dconstipation

Mfrac14

sponta

induced

additi

onalla

xative

Cfrac14

subcuta

aldesig

rvention

variable

Results

Random

cebo-c

double

patients

(Nfrac14

iddependence

(Nfrac14

imopan

patients

within

8hours

patients

8hours

imopan

respective

random

cebo-c

double

noncancer

imopan

Change

imopan

(thorn17

imopan

ID(thorn

imopan

ID(thorn

Webste

random

cebo-c

double

patients

noncancer

imopan

patients

inbaselin

imopan

Jansen

Random

cebo-c

double

patients

noncancer

imopan

patients

sponders

inboth

imopan

tistically

BIDfrac14

edaily

ICfrac14

id-induce

dconstipation

QIDfrac14

Mfrac14

sponta

induce

additi

onalla

xative

Disease

Antagonists

Acknowledgments

182S11ndash8

20002019ndash26

611181ndash7

71425ndash33

10397ndash401

97129ndash34

Sci 2014132557ndash68

1997113409ndash14

292G377ndash84

20453ndash8

47230ndash6

144218ndash38

APPENDIX

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 064

1000 0010

1000 910

1000 460

1000 0100

symptoms

1000 073

613 136

symptoms

1000 0100

1000 1000

1000 460

propulsive motility

1000 055

defecation

1000 0100

therapeutic choices

1000 0100

1000 0010 010

1000 046 55

1000 091 37

1000 0010 010

910 0010 010

1000 0100 19

(continued)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 1000 100

with chronic pain

1000 1000 36

been raised

1000 1000 100

1000 1000

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

aldesig

rvention

variable

Results

Random

double

noncancer

patients

ldquocle

patients

baselin

Results

BIDfrac14

edaily

ICfrac14

id-induce

dconstipation

Mfrac14

sponta

induced

additi

onalla

xative

Mfrac14

aldesig

rvention

Results

Random

ddouble

epatients

noncancer

ldquowith

equency

idusage

xone-t

patients

frequency

patient

3patients

experienced

rsalof

random

lleltr

patients

noncancer

ldquowith

longed-r

oxycodonen

longed-r

oxycodonep

lacebo

random

findin

cebo-c

lleltr

patients

cancer

ldquowith

concom

constipationrdquo

oxycodone

ependent

random

cebo-c

lleltr

patients

noncancer

longed-r

oxycodone

60ndash80

longed-r

oxycodonep

lacebo

reduced

in2009

random

cebo-c

lleltr

patients

modera

cancer

longed-r

oxycodone)

longed-r

oxycodonep

lacebo

laxative

innalo

edzai2012

[3353]

Ifrac14B

Function

OICfrac14

dconstipation

Mfrac14

sponta

induce

additi

laxative

Mfrac14

TIDfrac14

xegolfo

rvention

Results

random

dose-f

cebo-c

llelgro

patients

cancer-

xegol(5

nchange

baselin

(Pfrac14

Webste

enticalphase

random

double

llelgro

atients

noncancer

response

final4

weeks)

(Pfrac14

inboth

random

llelgro

patients

noncancer

xegol25

0ndash10

eequiv

Long-t

rabili

occurr

frequently

inalpain

nausea

headache

Webste

AEfrac14

Mfrac14

sponta

induced

additi

onalla

xative

OCfrac14

ylnaltr

aldesig

rvention

variable

Results

tochro

respective

Laxation

response

-coecal

transit

patients

treate

xation

response

-coecaltr

random

cebo-c

double

patients

illness

within

4hours

treatm

Laxation

within

4hours

respective

Random

double

cebo-c

patients

illness

laxative

treatm

initia

4hours

response

respective

ly(Pfrac14

patients

report

laxative

Random

cebo-c

patients

noncancer

ctions

leadin

within

4hours

within

4hours

(daily

altern

respective

(continued)

aldesig

rvention

variable

Results

random

double

llel-gro

cebo-c

patients

hopedic

cedure

likely

ization

Once-d

laxation

patients

experiencin

laxation

within

4hours

Laxation

within

2hours

(Pfrac14

4hours

(Pfrac14

laxation

(Pfrac14

OICfrac14

id-induce

dconstipation

Mfrac14

sponta

induced

additi

onalla

xative

Cfrac14

subcuta

aldesig

rvention

variable

Results

Random

cebo-c

double

patients

(Nfrac14

iddependence

(Nfrac14

imopan

patients

within

8hours

patients

8hours

imopan

respective

random

cebo-c

double

noncancer

imopan

Change

imopan

(thorn17

imopan

ID(thorn

imopan

ID(thorn

Webste

random

cebo-c

double

patients

noncancer

imopan

patients

inbaselin

imopan

Jansen

Random

cebo-c

double

patients

noncancer

imopan

patients

sponders

inboth

imopan

tistically

BIDfrac14

edaily

ICfrac14

id-induce

dconstipation

QIDfrac14

Mfrac14

sponta

induce

additi

onalla

xative

Disease

Antagonists

Acknowledgments

182S11ndash8

20002019ndash26

611181ndash7

71425ndash33

10397ndash401

97129ndash34

Sci 2014132557ndash68

1997113409ndash14

292G377ndash84

20453ndash8

47230ndash6

144218ndash38

APPENDIX

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 064

1000 0010

1000 910

1000 460

1000 0100

symptoms

1000 073

613 136

symptoms

1000 0100

1000 1000

1000 460

propulsive motility

1000 055

defecation

1000 0100

therapeutic choices

1000 0100

1000 0010 010

1000 046 55

1000 091 37

1000 0010 010

910 0010 010

1000 0100 19

(continued)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 1000 100

with chronic pain

1000 1000 36

been raised

1000 1000 100

1000 1000

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

aldesig

rvention

Results

Random

ddouble

epatients

noncancer

ldquowith

equency

idusage

xone-t

patients

frequency

patient

3patients

experienced

rsalof

random

lleltr

patients

noncancer

ldquowith

longed-r

oxycodonen

longed-r

oxycodonep

lacebo

random

findin

cebo-c

lleltr

patients

cancer

ldquowith

concom

constipationrdquo

oxycodone

ependent

random

cebo-c

lleltr

patients

noncancer

longed-r

oxycodone

60ndash80

longed-r

oxycodonep

lacebo

reduced

in2009

random

cebo-c

lleltr

patients

modera

cancer

longed-r

oxycodone)

longed-r

oxycodonep

lacebo

laxative

innalo

edzai2012

[3353]

Ifrac14B

Function

OICfrac14

dconstipation

Mfrac14

sponta

induce

additi

laxative

Mfrac14

TIDfrac14

xegolfo

rvention

Results

random

dose-f

cebo-c

llelgro

patients

cancer-

xegol(5

nchange

baselin

(Pfrac14

Webste

enticalphase

random

double

llelgro

atients

noncancer

response

final4

weeks)

(Pfrac14

inboth

random

llelgro

patients

noncancer

xegol25

0ndash10

eequiv

Long-t

rabili

occurr

frequently

inalpain

nausea

headache

Webste

AEfrac14

Mfrac14

sponta

induced

additi

onalla

xative

OCfrac14

ylnaltr

aldesig

rvention

variable

Results

tochro

respective

Laxation

response

-coecal

transit

patients

treate

xation

response

-coecaltr

random

cebo-c

double

patients

illness

within

4hours

treatm

Laxation

within

4hours

respective

Random

double

cebo-c

patients

illness

laxative

treatm

initia

4hours

response

respective

ly(Pfrac14

patients

report

laxative

Random

cebo-c

patients

noncancer

ctions

leadin

within

4hours

within

4hours

(daily

altern

respective

(continued)

aldesig

rvention

variable

Results

random

double

llel-gro

cebo-c

patients

hopedic

cedure

likely

ization

Once-d

laxation

patients

experiencin

laxation

within

4hours

Laxation

within

2hours

(Pfrac14

4hours

(Pfrac14

laxation

(Pfrac14

OICfrac14

id-induce

dconstipation

Mfrac14

sponta

induced

additi

onalla

xative

Cfrac14

subcuta

aldesig

rvention

variable

Results

Random

cebo-c

double

patients

(Nfrac14

iddependence

(Nfrac14

imopan

patients

within

8hours

patients

8hours

imopan

respective

random

cebo-c

double

noncancer

imopan

Change

imopan

(thorn17

imopan

ID(thorn

imopan

ID(thorn

Webste

random

cebo-c

double

patients

noncancer

imopan

patients

inbaselin

imopan

Jansen

Random

cebo-c

double

patients

noncancer

imopan

patients

sponders

inboth

imopan

tistically

BIDfrac14

edaily

ICfrac14

id-induce

dconstipation

QIDfrac14

Mfrac14

sponta

induce

additi

onalla

xative

Disease

Antagonists

Acknowledgments

182S11ndash8

20002019ndash26

611181ndash7

71425ndash33

10397ndash401

97129ndash34

Sci 2014132557ndash68

1997113409ndash14

292G377ndash84

20453ndash8

47230ndash6

144218ndash38

APPENDIX

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 064

1000 0010

1000 910

1000 460

1000 0100

symptoms

1000 073

613 136

symptoms

1000 0100

1000 1000

1000 460

propulsive motility

1000 055

defecation

1000 0100

therapeutic choices

1000 0100

1000 0010 010

1000 046 55

1000 091 37

1000 0010 010

910 0010 010

1000 0100 19

(continued)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 1000 100

with chronic pain

1000 1000 36

been raised

1000 1000 100

1000 1000

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

xegolfo

rvention

Results

random

dose-f

cebo-c

llelgro

patients

cancer-

xegol(5

nchange

baselin

(Pfrac14

Webste

enticalphase

random

double

llelgro

atients

noncancer

response

final4

weeks)

(Pfrac14

inboth

random

llelgro

patients

noncancer

xegol25

0ndash10

eequiv

Long-t

rabili

occurr

frequently

inalpain

nausea

headache

Webste

AEfrac14

Mfrac14

sponta

induced

additi

onalla

xative

OCfrac14

ylnaltr

aldesig

rvention

variable

Results

tochro

respective

Laxation

response

-coecal

transit

patients

treate

xation

response

-coecaltr

random

cebo-c

double

patients

illness

within

4hours

treatm

Laxation

within

4hours

respective

Random

double

cebo-c

patients

illness

laxative

treatm

initia

4hours

response

respective

ly(Pfrac14

patients

report

laxative

Random

cebo-c

patients

noncancer

ctions

leadin

within

4hours

within

4hours

(daily

altern

respective

(continued)

aldesig

rvention

variable

Results

random

double

llel-gro

cebo-c

patients

hopedic

cedure

likely

ization

Once-d

laxation

patients

experiencin

laxation

within

4hours

Laxation

within

2hours

(Pfrac14

4hours

(Pfrac14

laxation

(Pfrac14

OICfrac14

id-induce

dconstipation

Mfrac14

sponta

induced

additi

onalla

xative

Cfrac14

subcuta

aldesig

rvention

variable

Results

Random

cebo-c

double

patients

(Nfrac14

iddependence

(Nfrac14

imopan

patients

within

8hours

patients

8hours

imopan

respective

random

cebo-c

double

noncancer

imopan

Change

imopan

(thorn17

imopan

ID(thorn

imopan

ID(thorn

Webste

random

cebo-c

double

patients

noncancer

imopan

patients

inbaselin

imopan

Jansen

Random

cebo-c

double

patients

noncancer

imopan

patients

sponders

inboth

imopan

tistically

BIDfrac14

edaily

ICfrac14

id-induce

dconstipation

QIDfrac14

Mfrac14

sponta

induce

additi

onalla

xative

Disease

Antagonists

Acknowledgments

182S11ndash8

20002019ndash26

611181ndash7

71425ndash33

10397ndash401

97129ndash34

Sci 2014132557ndash68

1997113409ndash14

292G377ndash84

20453ndash8

47230ndash6

144218ndash38

APPENDIX

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 064

1000 0010

1000 910

1000 460

1000 0100

symptoms

1000 073

613 136

symptoms

1000 0100

1000 1000

1000 460

propulsive motility

1000 055

defecation

1000 0100

therapeutic choices

1000 0100

1000 0010 010

1000 046 55

1000 091 37

1000 0010 010

910 0010 010

1000 0100 19

(continued)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 1000 100

with chronic pain

1000 1000 36

been raised

1000 1000 100

1000 1000

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

ylnaltr

aldesig

rvention

variable

Results

tochro

respective

Laxation

response

-coecal

transit

patients

treate

xation

response

-coecaltr

random

cebo-c

double

patients

illness

within

4hours

treatm

Laxation

within

4hours

respective

Random

double

cebo-c

patients

illness

laxative

treatm

initia

4hours

response

respective

ly(Pfrac14

patients

report

laxative

Random

cebo-c

patients

noncancer

ctions

leadin

within

4hours

within

4hours

(daily

altern

respective

(continued)

aldesig

rvention

variable

Results

random

double

llel-gro

cebo-c

patients

hopedic

cedure

likely

ization

Once-d

laxation

patients

experiencin

laxation

within

4hours

Laxation

within

2hours

(Pfrac14

4hours

(Pfrac14

laxation

(Pfrac14

OICfrac14

id-induce

dconstipation

Mfrac14

sponta

induced

additi

onalla

xative

Cfrac14

subcuta

aldesig

rvention

variable

Results

Random

cebo-c

double

patients

(Nfrac14

iddependence

(Nfrac14

imopan

patients

within

8hours

patients

8hours

imopan

respective

random

cebo-c

double

noncancer

imopan

Change

imopan

(thorn17

imopan

ID(thorn

imopan

ID(thorn

Webste

random

cebo-c

double

patients

noncancer

imopan

patients

inbaselin

imopan

Jansen

Random

cebo-c

double

patients

noncancer

imopan

patients

sponders

inboth

imopan

tistically

BIDfrac14

edaily

ICfrac14

id-induce

dconstipation

QIDfrac14

Mfrac14

sponta

induce

additi

onalla

xative

Disease

Antagonists

Acknowledgments

182S11ndash8

20002019ndash26

611181ndash7

71425ndash33

10397ndash401

97129ndash34

Sci 2014132557ndash68

1997113409ndash14

292G377ndash84

20453ndash8

47230ndash6

144218ndash38

APPENDIX

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 064

1000 0010

1000 910

1000 460

1000 0100

symptoms

1000 073

613 136

symptoms

1000 0100

1000 1000

1000 460

propulsive motility

1000 055

defecation

1000 0100

therapeutic choices

1000 0100

1000 0010 010

1000 046 55

1000 091 37

1000 0010 010

910 0010 010

1000 0100 19

(continued)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 1000 100

with chronic pain

1000 1000 36

been raised

1000 1000 100

1000 1000

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

aldesig

rvention

variable

Results

random

double

llel-gro

cebo-c

patients

hopedic

cedure

likely

ization

Once-d

laxation

patients

experiencin

laxation

within

4hours

Laxation

within

2hours

(Pfrac14

4hours

(Pfrac14

laxation

(Pfrac14

OICfrac14

id-induce

dconstipation

Mfrac14

sponta

induced

additi

onalla

xative

Cfrac14

subcuta

aldesig

rvention

variable

Results

Random

cebo-c

double

patients

(Nfrac14

iddependence

(Nfrac14

imopan

patients

within

8hours

patients

8hours

imopan

respective

random

cebo-c

double

noncancer

imopan

Change

imopan

(thorn17

imopan

ID(thorn

imopan

ID(thorn

Webste

random

cebo-c

double

patients

noncancer

imopan

patients

inbaselin

imopan

Jansen

Random

cebo-c

double

patients

noncancer

imopan

patients

sponders

inboth

imopan

tistically

BIDfrac14

edaily

ICfrac14

id-induce

dconstipation

QIDfrac14

Mfrac14

sponta

induce

additi

onalla

xative

Disease

Antagonists

Acknowledgments

182S11ndash8

20002019ndash26

611181ndash7

71425ndash33

10397ndash401

97129ndash34

Sci 2014132557ndash68

1997113409ndash14

292G377ndash84

20453ndash8

47230ndash6

144218ndash38

APPENDIX

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 064

1000 0010

1000 910

1000 460

1000 0100

symptoms

1000 073

613 136

symptoms

1000 0100

1000 1000

1000 460

propulsive motility

1000 055

defecation

1000 0100

therapeutic choices

1000 0100

1000 0010 010

1000 046 55

1000 091 37

1000 0010 010

910 0010 010

1000 0100 19

(continued)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 1000 100

with chronic pain

1000 1000 36

been raised

1000 1000 100

1000 1000

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

aldesig

rvention

variable

Results

Random

cebo-c

double

patients

(Nfrac14

iddependence

(Nfrac14

imopan

patients

within

8hours

patients

8hours

imopan

respective

random

cebo-c

double

noncancer

imopan

Change

imopan

(thorn17

imopan

ID(thorn

imopan

ID(thorn

Webste

random

cebo-c

double

patients

noncancer

imopan

patients

inbaselin

imopan

Jansen

Random

cebo-c

double

patients

noncancer

imopan

patients

sponders

inboth

imopan

tistically

BIDfrac14

edaily

ICfrac14

id-induce

dconstipation

QIDfrac14

Mfrac14

sponta

induce

additi

onalla

xative

Disease

Antagonists

Acknowledgments

182S11ndash8

20002019ndash26

611181ndash7

71425ndash33

10397ndash401

97129ndash34

Sci 2014132557ndash68

1997113409ndash14

292G377ndash84

20453ndash8

47230ndash6

144218ndash38

APPENDIX

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 064

1000 0010

1000 910

1000 460

1000 0100

symptoms

1000 073

613 136

symptoms

1000 0100

1000 1000

1000 460

propulsive motility

1000 055

defecation

1000 0100

therapeutic choices

1000 0100

1000 0010 010

1000 046 55

1000 091 37

1000 0010 010

910 0010 010

1000 0100 19

(continued)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 1000 100

with chronic pain

1000 1000 36

been raised

1000 1000 100

1000 1000

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

Disease

Antagonists

Acknowledgments

182S11ndash8

20002019ndash26

611181ndash7

71425ndash33

10397ndash401

97129ndash34

Sci 2014132557ndash68

1997113409ndash14

292G377ndash84

20453ndash8

47230ndash6

144218ndash38

APPENDIX

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 064

1000 0010

1000 910

1000 460

1000 0100

symptoms

1000 073

613 136

symptoms

1000 0100

1000 1000

1000 460

propulsive motility

1000 055

defecation

1000 0100

therapeutic choices

1000 0100

1000 0010 010

1000 046 55

1000 091 37

1000 0010 010

910 0010 010

1000 0100 19

(continued)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 1000 100

with chronic pain

1000 1000 36

been raised

1000 1000 100

1000 1000

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

Acknowledgments

182S11ndash8

20002019ndash26

611181ndash7

71425ndash33

10397ndash401

97129ndash34

Sci 2014132557ndash68

1997113409ndash14

292G377ndash84

20453ndash8

47230ndash6

144218ndash38

APPENDIX

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 064

1000 0010

1000 910

1000 460

1000 0100

symptoms

1000 073

613 136

symptoms

1000 0100

1000 1000

1000 460

propulsive motility

1000 055

defecation

1000 0100

therapeutic choices

1000 0100

1000 0010 010

1000 046 55

1000 091 37

1000 0010 010

910 0010 010

1000 0100 19

(continued)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 1000 100

with chronic pain

1000 1000 36

been raised

1000 1000 100

1000 1000

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

Acknowledgments

182S11ndash8

20002019ndash26

611181ndash7

71425ndash33

10397ndash401

97129ndash34

Sci 2014132557ndash68

1997113409ndash14

292G377ndash84

20453ndash8

47230ndash6

144218ndash38

APPENDIX

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 064

1000 0010

1000 910

1000 460

1000 0100

symptoms

1000 073

613 136

symptoms

1000 0100

1000 1000

1000 460

propulsive motility

1000 055

defecation

1000 0100

therapeutic choices

1000 0100

1000 0010 010

1000 046 55

1000 091 37

1000 0010 010

910 0010 010

1000 0100 19

(continued)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 1000 100

with chronic pain

1000 1000 36

been raised

1000 1000 100

1000 1000

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

20002019ndash26

611181ndash7

71425ndash33

10397ndash401

97129ndash34

Sci 2014132557ndash68

1997113409ndash14

292G377ndash84

20453ndash8

47230ndash6

144218ndash38

APPENDIX

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 064

1000 0010

1000 910

1000 460

1000 0100

symptoms

1000 073

613 136

symptoms

1000 0100

1000 1000

1000 460

propulsive motility

1000 055

defecation

1000 0100

therapeutic choices

1000 0100

1000 0010 010

1000 046 55

1000 091 37

1000 0010 010

910 0010 010

1000 0100 19

(continued)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 1000 100

with chronic pain

1000 1000 36

been raised

1000 1000 100

1000 1000

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

97129ndash34

Sci 2014132557ndash68

1997113409ndash14

292G377ndash84

20453ndash8

47230ndash6

144218ndash38

APPENDIX

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 064

1000 0010

1000 910

1000 460

1000 0100

symptoms

1000 073

613 136

symptoms

1000 0100

1000 1000

1000 460

propulsive motility

1000 055

defecation

1000 0100

therapeutic choices

1000 0100

1000 0010 010

1000 046 55

1000 091 37

1000 0010 010

910 0010 010

1000 0100 19

(continued)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 1000 100

with chronic pain

1000 1000 36

been raised

1000 1000 100

1000 1000

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

97129ndash34

Sci 2014132557ndash68

1997113409ndash14

292G377ndash84

20453ndash8

47230ndash6

144218ndash38

APPENDIX

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 064

1000 0010

1000 910

1000 460

1000 0100

symptoms

1000 073

613 136

symptoms

1000 0100

1000 1000

1000 460

propulsive motility

1000 055

defecation

1000 0100

therapeutic choices

1000 0100

1000 0010 010

1000 046 55

1000 091 37

1000 0010 010

910 0010 010

1000 0100 19

(continued)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 1000 100

with chronic pain

1000 1000 36

been raised

1000 1000 100

1000 1000

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

97129ndash34

Sci 2014132557ndash68

1997113409ndash14

292G377ndash84

20453ndash8

47230ndash6

144218ndash38

APPENDIX

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 064

1000 0010

1000 910

1000 460

1000 0100

symptoms

1000 073

613 136

symptoms

1000 0100

1000 1000

1000 460

propulsive motility

1000 055

defecation

1000 0100

therapeutic choices

1000 0100

1000 0010 010

1000 046 55

1000 091 37

1000 0010 010

910 0010 010

1000 0100 19

(continued)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 1000 100

with chronic pain

1000 1000 36

been raised

1000 1000 100

1000 1000

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

Sci 2014132557ndash68

1997113409ndash14

292G377ndash84

20453ndash8

47230ndash6

144218ndash38

APPENDIX

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 064

1000 0010

1000 910

1000 460

1000 0100

symptoms

1000 073

613 136

symptoms

1000 0100

1000 1000

1000 460

propulsive motility

1000 055

defecation

1000 0100

therapeutic choices

1000 0100

1000 0010 010

1000 046 55

1000 091 37

1000 0010 010

910 0010 010

1000 0100 19

(continued)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 1000 100

with chronic pain

1000 1000 36

been raised

1000 1000 100

1000 1000

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

144218ndash38

APPENDIX

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 064

1000 0010

1000 910

1000 460

1000 0100

symptoms

1000 073

613 136

symptoms

1000 0100

1000 1000

1000 460

propulsive motility

1000 055

defecation

1000 0100

therapeutic choices

1000 0100

1000 0010 010

1000 046 55

1000 091 37

1000 0010 010

910 0010 010

1000 0100 19

(continued)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 1000 100

with chronic pain

1000 1000 36

been raised

1000 1000 100

1000 1000

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

APPENDIX

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 064

1000 0010

1000 910

1000 460

1000 0100

symptoms

1000 073

613 136

symptoms

1000 0100

1000 1000

1000 460

propulsive motility

1000 055

defecation

1000 0100

therapeutic choices

1000 0100

1000 0010 010

1000 046 55

1000 091 37

1000 0010 010

910 0010 010

1000 0100 19

(continued)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 1000 100

with chronic pain

1000 1000 36

been raised

1000 1000 100

1000 1000

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

APPENDIX

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 064

1000 0010

1000 910

1000 460

1000 0100

symptoms

1000 073

613 136

symptoms

1000 0100

1000 1000

1000 460

propulsive motility

1000 055

defecation

1000 0100

therapeutic choices

1000 0100

1000 0010 010

1000 046 55

1000 091 37

1000 0010 010

910 0010 010

1000 0100 19

(continued)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 1000 100

with chronic pain

1000 1000 36

been raised

1000 1000 100

1000 1000

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 064

1000 0010

1000 910

1000 460

1000 0100

symptoms

1000 073

613 136

symptoms

1000 0100

1000 1000

1000 460

propulsive motility

1000 055

defecation

1000 0100

therapeutic choices

1000 0100

1000 0010 010

1000 046 55

1000 091 37

1000 0010 010

910 0010 010

1000 0100 19

(continued)

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 1000 100

with chronic pain

1000 1000 36

been raised

1000 1000 100

1000 1000

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

Statement

Level of agreement

Agreeneutral

disagree

Level of evidence

Strong moderate

Strength of

recommendation

Strong weak

1000 1000 100

with chronic pain

1000 1000 36

been raised

1000 1000 100

1000 1000

on QoL

1000 370 100

pnw255-TF1

pnw255-TF2

pnw255-TF3

pnw255-TF4

pnw255-TF5

Documents

Aalborg Universitet Opioid-Induced Constipation and Bowel ... · Introduction Pain, when not effectively treated and relieved, has det-rimental effects on all aspects of a patient’s