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Moving Beyond Laxatives in

New Targets,NewStrategies,NewOutcomes


New Targets, New Strategies, New Outcomes

Activity Description

The majority of patients treated with opioid therapyfor cancer and non-cancer pain experience opioid-induced constipation (OIC). This condition is nottrivial as it affects the patient’s quality of life and canlead them to reduce, discontinue, or change effectiveanalgesic therapy. The spectrum of laxative classescurrently available do not provide effective results inthis setting, primarily because they do not addressthe mechanisms by which opioids cause OIC.Research advances have improved the understandingof those underlying mechanisms and have resultedin the identification of new pharmacologic agentsthat target the μ (mu)-opioid receptor interactionwhile maintaining the analgesic benefit of the opioidand minimizing the risk of withdrawal.

Newer ion channel agents may also be effective asmono- or combination therapy for these patients.Results from large clinical trials of these nextgeneration agents should help provide theframework for an evidence-based approach tomanaging OIC, which is currently not available. In theabsence of guidelines, the current best practice is toassess and treat these patients early.

This monograph is the first activity in a 3-moduleseries that reviews the current and evolvingapproaches to managing OIC through the use ofpatient vignettes and faculty-facilitated audio Q&As.

Activity Faculty

Mary M. Bridgeman, PharmD, BCPS, CGPClinical Associate ProfessorErnest Mario School of PharmacyRutgers, The State University of New JerseyInternal Medicine Clinical PharmacistRobert Wood Johnson University HospitalNew Brunswick, New Jersey

William Chey, MD, FACGProfessor of MedicineDirector, GI Physiology LaboratoryCo-Director, Michigan Bowel Control ProgramUniversity of MichiganAnn Arbor, Michigan

Target Audience

This enduring activity has been designed to meet theeducational needs of gastroenterologists, family andinternal medicine physicians, nurse practitioners,physician assistants, and pharmacists who providecare to patients with opioid-induced constipation.

Learning Objectives

As a result of participating in the activity, learnersshould be better able to:

• Differentiate the mechanism of OIC from othertypes of constipation and opioid bowel dysfunctionto guide treatment in practice.

• Address patients’ needs for simple communicationby providing new strategies for healthcareprofessionals to describe the signs, symptoms, andeffective management of OIC

• Implement evidence-based practices toprophylactically treat OIC

• Compare and contrast newer agents for thetreatment of OIC in terms of safety, efficacy, modeof administration and the patient populations forwhich they are approved

Accreditation and Credit Designation

This activity has been planned and implemented inaccordance with the accreditation requirements andpolicies of the Accreditation Council for ContinuingMedical Education (ACCME) through the jointprovidership of the American Academy of CME, Inc.,(Academy) and PeerXChange. The AmericanAcademy of CME, Inc., is accredited by the ACCME toprovide continuing medical education for physicians.

The American Academy of CME, Inc., designates thisenduring material for a maximum of 1.00 AMA PRACategory 1 CreditsTM. Physicians should claim only the

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credit commensurate with the extent of theirparticipation in the activity.

American Academy of CME, Inc. isaccredited by the Accreditation Council forPharmacy Education (ACPE) as a provider

of continuing pharmacy education.

This activity provides 1.0 contact hours (0.1 CEUs) ofcontinuing education credit. ACPE Universal ActivityNumber: 0297-9999-14-036-H01-P, Application-based Activity.

Disclosure Statement

According to the disclosure policy of the Academy,all faculty, planning committee members, editors,managers and other individuals who are in a positionto control content are required to disclose anyrelevant relationships with any commercial interestsrelated to this activity. The existence of theseinterests or relationships is not viewed as implyingbias or decreasing the value of the presentation. Alleducational materials are reviewed for fair balance,scientific objectivity and levels of evidence.Disclosures are as follows:

Mary M. Bridgeman, PharmD, BCPS, CGP

Nature of Relationship Commercial Entity

Advisory Board: Merck Consumer Caremarketing purposes

Grant Recipient/ CareFusion Foundation 2014Research Support Clinical Excellence Grant (PI) (Funds paid to Robert Wood JohnsonUniversity Hospital Foundation)

Other Relationships Speakers’ Bureau (Non-Promotional): AmerisourceBergen Corporation

William Chey, MD, FACG

Nature of Relationship Commercial Entity

Advisory Board: Synthetic Biologicsscientific information

Consultant: clinical AstraZeneca, Entera Health,trial design Ferring Pharmaceuticals,

Forest Laboratories, Furiex Pharmaceuticals, IronwoodPharmaceuticals, Perrigo Company, PrometheusLaboratories, Nestlé,SmithKline, SucampoPharmaceuticals, TakedaPharmaceuticals

Grant Recipient/ Ironwood Pharmaceuticals,Research Support Prometheus Laboratories,(Funds paid to the Nestlé, Perrigo CompanyUniversity of Michigan)

Independent Clinical Peer Reviewer

Steven R. Peikin, MD, Professor of Medicine, Head,Division of Gastroenterology and Liver Diseases,Cooper Medical School of Rowan University andCooper University Health Care, Camden, New Jersey:No relevant financial relationships with anycommercial interests.

John J.D. Juchniewicz, MCIS, CCMEP, AmericanAcademy of CME and Deborah Dean, MichelleYechout, and Bret Fulton, RPh (Editorial AssistanceProvided). PeerXChange: No relevant financialrelationships with any commercial interests.

This activity will review off-label or investigationalinformation.

Off-label/Under Investigation

Linaclotide, is a guanylate cyclase-C agonist used for the treatment of irritable bowel syndrome withconstipation and chronic idiopathic constipation.

Prucalopride, is a 5-HT4 agonist approved in Europe forthe treatment of chronic constipation in women whohave not responded to the use of laxatives.

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Tapentadol, is a dual μ-opioid agonist andnorepinephrine reuptake inhibitor used to treatmoderate to severe pain.

This activity is designed for use by healthcareprofessionals for educational purposes only. Theopinions expressed in this educational activity arethose of the faculty, and do not represent those ofthe Academy or PeerXChange. This activity isintended as a supplement to existing knowledge,published information, and practice guidelines.Learners should appraise the information presentedcritically, and draw conclusions only after carefulconsideration of all available scientific information.

How to Earn CE Credit

During the period December 12, 2014 throughDecember 12, 2015, participants must 1) read thelearning objectives and faculty disclosures; 2) studythe educational activity; and 3) complete the pre-test, post-test and evaluation form. To answer thequestions, click on your selected choice for eachanswer then proceed to the next question. Oncecompleted, submit it and your post-test willautomatically be graded. Once you successfullycomplete the post-test (score of 70% or higher) andactivity evaluation, your Statement of Credit will bemade available immediately. Click on View Certificateand print the Statement of Credit for your records.

Audio Instructions

This CME/CPE certified activity includes MP3 audioclips interspersed throughout. When you encountera faculty Q&A, click the audio “icon” to begin listeningto the faculty respond to the Q&A.

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Contact

For any questions, please contact:[email protected]

Copyright

© 2014. This CME/CE-certified activity is held ascopyrighted © by American Academy of CME, Inc.and PeerXChange. Through this notice, the Academyand PeerXChange grant permission of its use foreducational purposes only. These materials may notbe used, in whole or in part, for any commercialpurposes without prior permission in writing fromthe copyright owner(s).

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Introduction

Chronic pain is a common problem affecting anestimated 15% of the population with the prevalencebeing even higher in many patient groups (eg,military veterans, cancer patients).1 For patients whosuffer from moderate-to-severe chronic pain, opioidanalgesics are the mainstay of treatment.2 Opioidsare an effective therapy for these patients, withestimates indicating that approximately 3% of adults(7-8 million people) receive long-term opioidtherapy for chronic pain.2 Chronic pain can includeconditions such as traumatic injury, musculoskeletalor back pain, neuropathic pain, fibromyalgia, andosteoarthritis pain.

There has been a dramatic increase in the chronicuse of opiates in the US over the last several years,although the rate appears to have leveled off inrecent years. In 2009, more than 250 millionprescriptions were written for opioids in the US,including 234 million for immediate-releasepreparations and 22.9 million for long-acting agents.This represents a 48% increase from 2000, where thetotal number of short-acting and long-acting agentswere 164.8 and 9.3 million, respectively.3 The mostcommon long-acting agents were extended-releaseoxycodone (34%), transdermal fentanyl (22%), andextended-release morphine (22%).3 Roughly 3.8million patients are prescribed long-acting orextended-release opioids annually, representing anincrease from 2.7 million in 2000 (Figure 1).3

Burden of Opioid-Induced Constipation

While opiates are the gold standard for thetreatment of chronic pain, they are associated withadverse events that can compromise the therapeuticpotential of these agents. Gastrointestinal adverseevents are some of the most common anddebilitating events associated with chronic opiateuse. In particular, opioid-induced constipation (OIC)is a very common manifestation and, unlike otheradverse events (eg, nausea, sedation), theconstipating effects of opioids do not diminish withcontinued exposure. A meta-analysis of 11 trialsamong patients taking opiates for non-cancer painfor up to 8 weeks found that 41% of patientsexperienced OIC or other opiate bowel dysfunctioncompared with only 11% of placebo-treatedpatients.4 These results confirm the findings of thePROBE 1 survey conducted in patients from the USand Europe who reported taking daily oral opioidsand laxatives.5 The PROBE results indicated that 81%of patients had constipation and 45% had less than 3 spontaneous bowel movements (BMs) per week.5

Patients with OIC suffer from a range of symptomsthat diminish their quality of life (QoL) and ability toperform activities of daily living. These symptomsinclude abdominal pain, cramping, bloating, hardstools, straining, painful defecation, and an ongoingsense of incomplete evacuation.5,6 For example, alongitudinal study conducted in North America andEurope evaluating 500 patients with OIC found that the most important OIC symptoms werestraining/squeezing to pass a BM (82.6%), too hard BMs (75.1%), abdominal bloating (68.6%),incomplete BMs, (68.4%), painful BMs (66.9%),abdominal discomfort (64.1%), and too small BMs (63.3%).6

OIC frequently limits the utility of opioids in treatingchronic pain and increases the use of healthcare andalternative healthcare resources.5-7 An analysis ofclaims data found that opioid-treated patients with

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Figure 1. Total number of unique patients receivingextended-release/long-acting opioids in the US3

Num

ber o

f uni

que

patie

nts

(mill

ions

)

2002 2003 2004 2005 2006 2007 2008 2009

0.50

1.52

1

3.54

4.5

2.5 2.73.16 3.08 3.24

3.493.7

3.95 3.833



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constipation are more likely to switch opioid therapy(45% vs 28%; P<0.0001), had more emergencydepartment visits (1.69 vs 0.83; P<0.0001), moreoffice visits (29.1 vs 20.0; P<0.0001), higheroutpatient and ancillary care service costs ($15,164vs $8,512; P<0.0001), higher inpatient cost ($32,926vs $12,151; P<0.0001), and higher pharmacy-relatedcosts ($11,159 vs $7,644; P<0.0001) compared withcontrols without constipation.7 Patients treated withopioids for non-cancer pain commonly endureconstipation symptoms that limit their workproductivity and overall health-related quality of life.6

For example, the longitudinal study mentionedabove found that OIC was associated with a 9% lossin time worked, a 32% impairment while working(equivalent to 14 hours of lost productivity per week)and a 38% activity impairment.6

Many chronic pain patients with OIC alter ortemporarily abandon their opioids, tradingconstipation relief for pain. Others increase theiropioid dosage or rotate to a different opioid inresponse to increasing pain from OIC. However,changes in opioid dosing is associated withsignificant risk as studies have shown that opioiddose escalation, dose changes, and frequentrotation of opioids increases the risks of prescribingerror, patient dosing errors, opioid overdose, opioidrelated death, and other serious opioidtoxicities.2,6,8-10 In one study, 49% of patients withOIC reported that constipation was associated withmoderate to complete interference in how their painwas managed.6 In addition, 8% reported that theyhad changed how they had used their opioidmedication within the last 7 days in order to have abowel movement.6 In the PROBE study, one-third ofpatients had missed, decreased, or even stoppedusing opioids with the specific intent of inducing abowel movement. In these cases, 92% had anincrease in pain.5 Opioid-induced constipation canhave other, sometimes severe, consequencesincluding hemorrhoid formation, rectal pain andburning, bowel obstruction, and bowel perforation.11

Pathophysiology of OIC

Opioid receptors are widely distributed throughoutthe central and peripheral nervous system as well as the intestinal musculature.2 Endogenous opioidsin the gastrointestinal (GI) tract act via inhibition ofpropulsive motor activity and secretions, therebysuppressing intestinal motility.12 While three types ofopioid receptors have been identified in the GI tract(μ, κ, and δ), the GI effects of opioids appear to beprimarily mediated by μ (mu) receptors.11,12 Theaction of morphine at μ receptors results in aninhibitory effect on chloride secretion viasuppression of discharge from cholinergicsecretomotor neurons in the enteric nervoussystem.13 Consequently, there is an inhibition ofintestinal motility and a reduction in mucosalsecretions, thereby decreasing peristalsis andsecretions into the gut and increasing thereabsorption of fluid. This results in the formation of dry, hard stools that are difficult to pass and aprolongation of transit time. In addition, opioidsincrease anal sphincter tone and decrease reflexrelaxation which exacerbates the inability toevacuate the stool.11,12

Case Presentation

Margie is a 57 year-old female who is obese and hasrecently been diagnosed with degenerative discdisease. She experiences severe pain that interfereswith her activities of daily living. Chores around thehouse have become difficult to perform and she mustspend large amounts of time in a reclining position.She has diabetes of 10 years duration and a history of coronary artery disease. She has no history ofgastrointestinal disease and has generally had regularbowel movements. Her medications includemetformin, lisinopril, and atorvastatin. Until recently,she had relied on OTC analgesics such asacetaminophen and ibuprofen for relief of pain but thepain has become unbearable. Her physician prescribedextended-release oxycodone 30 mg every 12 hoursplus immediate-release oxycodone 10 mgadministered every 4-6 hours for breakthrough pain.



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Assessment of OIC

Despite the high prevalence of OIC among opioidusers, healthcare professionals are often notinquiring about or screening for constipation inpatients who are treated with opioids. In the NorthAmerican/European longitudinal study, only 63% ofpatients with OIC had discussed the condition with ahealthcare professional.6 A recent study explored theknowledge and practice patterns of more than 300US-based healthcare professionals (primary carephysicians [PCPs], n=101; pain specialists, n=151;nurse practitioners, n=75) with respect to thediagnosis and management of OIC in patients onchronic opioid therapy.14 Half of the PCPs and painspecialists initiated a prophylactic constipationregimen less than 40% of the time. Further, cliniciansmay not know how to differentiate OIC from othertypes of constipation.14 In this study, less than half(40% of pain specialists, 33% of PCPs) of thoseresponsible for making a diagnosis recognized thatOIC is a subset of opioid bowel dysfunction (OBD).14

Although constipation is fundamentally defined bythe patient, any patient who reports less than 3 BMsper week requires assessment.15 A thorough historyand examination is important. Possible causes ofconstipation (eg, opioid dose change, addition ofanother constipation-inducing medication, newbowel obstruction) should be evaluated.16 Thetemporal relationship between opioids andconstipation should be evaluated since not allpatients with constipation who are on opioidsnecessarily have OIC.17 Those with a longstandinghistory of constipation prior to the initiation ofopioids likely have non-opioid-related explanationscontributing to their constipation; while those with aclear temporal relationship are more likely to haveOIC. Patients may also have multiple causativefactors for constipation which could includesecondary causes (eg, medications, neuropathic ormyopathic disorders, endocrinopathies) or primarycauses (eg, irritable bowel syndrome, slow-transit

disorder, evacuation disorder).17 This heterogeneityand overlapping pathogenesis contributes to thedifficulty in managing patients and explains thedifferent types of patients seen in different practicesettings.

Once constipation is confirmed, an assessment ofbowel patterns and the impact of constipation onthe patient should be performed. The interviewshould elicit information regarding the frequencyand consistency of bowel movements, changes inbowel patterns, the level of discomfort and pain, thesensation of complete evacuation, the importance ofregular bowel movements to the patient, and anypsychosocial factors that may influence the ability todefecate.15 Key components to OIC management aresummarized in Table 1. Potential questions to askthe patient are described in Table 2.

Dr. Chey: What are the differences between the OIC patients seen by primary care physicians,oncologists, and pain specialists and those seen by gastroenterologists?

Table 1. Key components of the management ofconstipation15

Clinical Evaluation Checklist

� Constipation is fundamentally defined by the patient� Complaint of constipation and <3 BMs per week warrants evaluation� Thorough patient history and physical examination are important� Use checklist to assess causative factors and impact of constipation;

assessment should be ongoing� Ensure patient that privacy and comfort are important� Encourage increased fluid intake and physical activity� Avoid rectal intervention where possible but may be necessary when

medication is unsuccessful� Initiate prophylactic regimens in patients receiving chronic opioid therapy

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Management of OIC

General Approaches

Currently, there are no specific guidelines for themanagement of OIC in the United States. However,the European Association of Palliative Care (EAPC)has published guidelines for the treatment ofadverse effects associated with opioids.19 RegardingOIC, the EAPC recommends a variety of possiblestrategies including the routine prophylactic use oflaxatives, reducing the opioid dose, rotating opioids,changing the route of administration, and the use ofsymptomatic therapies.19 However, the efficacy ofthese strategies is not established. Dose reduction islikely to be associated with a decrease in pain reliefand there is a lack of randomized trials to supportswitching opioids as a means of reducing OIC.Further, switching to an alternative opioid may notbe effective as data from a large retrospective studyin 12,000 terminally ill patients found no differencein the constipation severity between sustained-release morphine, oxycodone, and transdermal

Table 2. Assessment of bowel function and impact on patient15,18

Frequency and consistency Importance of regularof bowel movements Discomfort and Pain bowel movements Influencing factorsWhen was your last BM? Is defecation painful, How important are regular What OTC and prescription medications

uncomfortable? bowel movements? are you taking?

What was the consistency What is the most distressing Do you have anxiety/concern What medications have you previouslyof the last stool? symptom (eg, frequency, about constipation? taken for constipation?

straining, hard stools, incomplete evacuation, pain, bloating, general discomfort)?

On average, how many BMs do you have each week?

How long have you had problems with constipation?

Is there blood/mucus in the stool?

Has the level of constipation/straining changed?

Was the last defecation characteristic of recent bowel habits?BM = bowel movement

Case Continuation: Initiation of Opioid Therapy

At the initiation of opioid therapy, Margie wascounseled on the potential for constipation with hernew pain regimen. She was told of the importance ofmaintaining adequate fluid intake and trying to initiatesome modest physical activity such as walking 30minutes 3 to 4 times per week. She was also initiatedon a stool softener/stimulant laxative combination(docusate/senna).

Dr. Bridgeman: What is the pharmacist’s role in providingpatient education in OIC?

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fentanyl.1 One exception may be tapentadol which isa dual μ-opioid agonist and norepinephrinereuptake inhibitor. Data suggest that tapentadol isassociated with less impairment of bowel functioncompared with oxycodone.1

Importance of Being Proactive

Since constipation is one of the most commonadverse events associated with opioids and theconstipating effects of these agents do not diminishwith continued exposure, a proactive approach topreventing/managing OIC is important. This isevidenced by guidelines from the American PainSociety and the American Academy of Pain Medicinewho have a strong recommendation that cliniciansshould anticipate, identify, and treat commonopioid-associated adverse effects.20 These guidelinesrecommend that a bowel regimen should beroutinely initiated prior to the development ofconstipation. Similarly, pain guidelines at MDAnderson Cancer Center recommend that allpatients receiving opioids should be started on alaxative bowel regimen and receive education forbowel management unless the patient has a pre-existing bowel obstruction or diarrhea.16

Improving the Healthcare Professional-Patient Relationship Improves Outcomes

Good provider/patient communication is importantto ensuring management plans are effectivelyimplemented and adhered to and that clinicaloutcomes are maximized. A meta-analysis of 22studies evaluated the effect of physician-patientcommunication on patient-related health outcomessuch as patient satisfaction, adherence to treatment,and patient comprehension.21 The analysis identifieda number of key verbal and nonverbal behaviors that

were positively associated with these outcomes(Table 3). Key verbal behaviors included empathy,reassurance and support, patient-centeredquestioning, explanations, humor, psychosocialdiscussion, providing health education andinformation sharing, friendliness, courtesy, orientingthe patient during the physical examination, andsummarization and clarification. Key non-verbalbehaviors associated with improved outcomesincluded head nodding, forward lean, direct (frontal)body orientation, uncrossed legs and arms, andsymmetry between the patient and clinician in bodyposition.21 These data suggest that providerinteraction skills (both verbal and nonverbal) andthe constructive reinforcement of positive behaviorsare important components of patient education andoverall management—improving patientsatisfaction, adherence to treatment, symptomresolution, and quality of life.

Dr. Chey: What are some practical tips when choosing aspecific treatment for a specific patient?

Table 3. Components of good communication andpatient-centered care22

Communication Checklist

� Allow patient to complete his/her opening statement� Elicit concerns and establish a rapport with patient� Use a combination of open-ended and closed-ended questions to

gather and clarify information� Identify and respond to the patient’s personal situation, beliefs

and values� Use language that the patient can understand to explain the diagnosis

and treatment plans� Check for patient understanding� Encourage the patient to participate in decisions and explore the

patient’s willingness and ability to follow care plans� Ask for other concerns the patient might have� Discuss follow-up activities expected of the patient before closing

the visit

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Nonpharmacologic Therapies

The use of lifestyle changes for the management ofOIC has not been well studied and when used alone,is unlikely to be effective for preventing OIC. However,lifestyle changes are reasonable to include in theoverall management plan. Adequate fluid intake,increased dietary fiber intake, and increased physicalactivity may provide some relief. Data suggest thatphysically active individuals are less likely toexperience constipation and that increased physicalactivity can improve bowel function in individualswho are constipated.1 Encouraging daily bowelmovements at the same time every day andeducation regarding the recognition of promptresponse to the urge to defecate is also important.1,12

Over-the-Counter Preparations

A number of over-the-counter laxatives and stoolsofteners are available (Table 4); but their efficacy inthe management of OIC is not established. Theseinclude stool softeners (eg, docusate sodium),stimulants (senna, bisacodyl), osmotic laxatives (eg,magnesium salts, lactulose, sorbitol, polyethyleneglycol [PEG]), soluble fiber (eg, psyllium seed), andenemas. While these agents are generally welltolerated; they can be associated with adverseeffects such as nausea, vomiting, diarrhea,abdominal pain, and electrolyte changes that havethe potential to cause patients to discontinuetreatment. Data from a survey of over 300 healthcareprofessionals (half of whom were pain specialists)indicated that the most commonly used agents forthe prophylaxis of OIC are stool softeners, osmoticlaxatives, and a high fiber diet.14 The main drivers forchoice of an OTC agent include bowel movementsymptoms, patient experience with previous anti-constipation preparations, patient characteristics,and patient preference.14 The use of bulk fiberlaxatives in patients with OIC should probably beavoided since these agents work by increasing stool

bulk, thereby distending the colon and stimulatingperistalsis. Since opioids prevent peristalsis of thisfiber-induced bulk, there is the potential forincreased abdominal pain and the potential forinducing bowel obstruction.11

Despite the wide availability of these laxative agents,most patients with OIC find it difficult to obtainrelief. In both the cancer and non-cancer painsettings, laxatives are generally ineffective becausethey do not address the underlying cause of OIC,which is the binding of opioid to μ-opioid receptors.Most of these agents have little data demonstratingefficacy although PEG has been shown to increase“nonhard” stools compared with placebo in patientswith methadone-induced constipation.15 Studies incancer and non-cancer pain settings consistentlyshow that the majority of patients receiving opioidtreatment develop OIC despite laxative use.5,6 Forexample, Coyne et al recently reported their findingsin a study of patients receiving opioids for non-cancer pain. Patients reported a mean of 1.4spontaneous bowel movements on average perweek; however, 83% reported wanting to have a BMat least once a day. Most patients used laxatives;60% used ≥1 OTC laxative and 19% used ≥1prescription laxative. Only 36% of OIC patientsreported no laxative use. Despite the use oflaxatives, almost all (97.7%) of the US patientsreported inadequate response after using at leastone laxative at least 4 times within the previous 2weeks and almost one-third (31.8%) reportedinadequate response after using 2 laxative agentsfrom different drug classes at least 4 times within theprevious 2 weeks.6

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Pharmacological Therapies

Advancements in the understanding of themechanism of constipation have led to thedevelopment of more targeted approaches thatspecifically counteract the effects of opioids in thegastrointestinal tract. Different strategies have beenevaluated to reduce the gastrointestinal effects ofopioids while maintaining their analgesic effect.

Currently, three agents are approved for thetreatment of opioid-induced constipation (Table 5).Lubiprostone is an oral ion channel activator that isapproved to treat adults with OIC in adults with

chronic non-cancer pain.23 Peripherally acting μ-opioid receptor antagonists (PAMORAs) have also been developed with the aim of blocking thebinding of opioid to μ-opioid receptors in thegastrointestinal tract. The PAMORAmethylnaltrexone bromide is a subcutaneouslyadministered drug approved for use in patients withadvanced illness receiving palliative care when theresponse to laxative therapy is not sufficient andalso for the treatment of OIC in patients with chronicnon-cancer pain. Most recently, the oral PAMORAnaloxegol was approved for the treatment of OIC inadults with chronic, non-cancer pain.

Ion Channel Activator: Lubiprostone

Lubiprostone is a prostone that activates type-2chloride channels in the intestine; thereby increasingthe secretion of fluid and electrolytes andaccelerating transit times in the small intestine andcolon.24 In vitro studies suggest that morphineinhibits chloride secretion via suppression ofcholinergic secretomotor neurons in the GI tract and

Table 4. Laxatives and stool softeners for the treatment of OIC12

Class Examples Mechanism of Action Adverse EffectsStool softeners/emollients Docusate sodium, dioctyl sodium Lubricates and softens stools Minimally absorbed and generally

well-tolerated; mild abdominal cramping Stimulants/irritants Senna, bisacodyl Alters intestinal mucosal Electrolyte imbalance, dermatitis,

permeability; stimulates muscle melanosis coliactivity and fluid secretions

Osmotic laxative Magnesium salts, lactulose, Osmotically-driven increase in Electrolyte imbalance, dehydration,sorbitol, glycerin fluid retention in the bowel lumen, excessive gas; hypermagnesemia,

resulting in increase in fluid hypocalcemia and hyperphosphatemiasecretion in the small intestine (primarily in patient with renal

dysfunction)Non-absorbable Polyethylene glycol Osmotically-driven increase in fluid Nausea, abdominal fullness, bloatingosmotic laxative retention in the bowel lumenBulk laxatives Psyllium seed, bran Increased fecal bulk and fluid Increased gas, bloating, bowel

retained in the bowel lumen obstruction (in presence of strictures),choking (if taken with inadequate fluid)

Enema Mineral oil, saline Reflex evacuation Dehydration, hypocalcemia andhyperphosphatemia (in patients withrenal dysfunction)

Case Continuation: 3-Month Follow-up

At her three-month follow-up appointment, Margie wasreluctant to discuss her bowel habits. However, aftersome gentle coaxing, she stated that she hasexperienced straining and painful BMs. She said thather bowel movements have decreased from almostdaily prior to initiating opioids to approximately 2 to 3BMs per week, currently.



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that lubiprostone counteracts this inhibition.24

Lubiprostone appears to be less effective againstmethadone-induced OIC compared with otheropioids. This appears to be because methadone, butnot morphine, inhibits lubiprostone-stimulatedCl(−) currents.25

The efficacy of lubiprostone in the treatment of OICin patients receiving opioids for chronic non-cancerpain who had been receiving stable opioid therapyfor at least 30 days was assessed in 3 randomized,double-blinded, placebo-controlled studies.23,26,27 Themean oral morphine equivalent daily dose rangedfrom 130 to 373 mg/day for those receivinglubiprostone and from 99 to 330 mg/day for thosereceiving placebo. All patients had documented OIC,defined as <3 spontaneous BMs per week with ≥25%of spontaneous BMs associated with ≥1 of thefollowing conditions: 1) hard to very hard stoolconsistency; 2) moderate to very severe straining;and/or 3) having a sensation of incompleteevacuation. Patients in all studies were randomizedto receive lubiprostone 24 mcg or placebo twicedaily. In the first study, which excluded patientsreceiving methadone, a significantly greaterproportion of patients receiving lubiprostone had aresponse (defined as ≥1 spontaneous BMimprovement from baseline for all treatment weeksand ≥3 spontaneous BMs/week for at least 9 of 12treatment weeks) compared with the placebo group(26.9% vs 18.6%; P=0.035).27 The other 2 studies didnot exclude patients taking methadone. In thesecond study, the mean changes from baseline inspontaneous BM frequency at week 8 (primaryendpoint) were 3.3 and 2.4 (P=0.004), respectively,for lubiprostone and placebo-treated patients.26 Thisstudy also found significant improvements versusplacebo in many constipation-related signs andsymptoms including abdominal discomfort,straining, constipation severity, and stoolconsistency.26 In the third study, there was nosignificant difference between the lubiprostone and

placebo groups for the primary endpoint, the meanchange from baseline in spontaneous BM frequencyat week 8 (2.7 vs 2.5, respectively).23

Lubiprostone appears to be well tolerated with mostadverse events being gastrointestinal and mild tomoderate in intensity. The most common adverseevents in placebo-controlled trials among patientsreceiving lubiprostone for OIC included nausea (11% vs 5%), diarrhea (8% vs 2%), and abdominalpain (4% vs 1%).23

PAMORAs: Alvimopan, Methylnaltrexone,Naloxegol

Alvimopan was an early PAMORA indicated toaccelerate the time to upper and lower GI recoveryfollowing surgeries.28 Early data29 suggest possibleefficacy for OIC but a Phase 3 trial30 found nosignificant benefit and further development for OIChas been discontinued. In addition, although acausal relationship was not demonstrated; there wasan increased risk of myocardial infarction in patientstreated with alvimopan.28 Because of this, there wassome concern that such cardiovascular effects maybe a class effect of PAMORAs. On June 12, 2014,however, an FDA panel ruled that there was notenough evidence to link the drug class withincreased cardiovascular events and advised againstrequiring large clinical trials to evaluate thecardiovascular risks of these drugs.31

Methylnaltrexone is a PAMORA that is administeredsubcutaneously. The quaternary amine structure ofmethylnaltrexone restricts the ability of the drug tocross the blood-brain barrier; thereby limiting theactivity of the drug to peripheral μ-opioid receptors.The efficacy and safety of the drug was evaluated intwo double-blind, placebo-controlled Phase 3 trialsin patients with OIC and advanced illness (primarilycancer). Patients were on a stable opioid regimenand (median morphine equivalent dose of 172mg/day) and had OIC defined as either <3 bowelmovements in the preceding week or no BM for >2



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days. Patients received either methylnaltrexone 0.15 mg/kg or 0.30 mg/kg or placebo. In the firststudy, a higher proportion of patients receivingmethylnaltrexone (62% for 0.15 mg/kg and 58% for0.3 mg/kg) had rescue-free laxation within 4 hours ofstudy medication (primary endpoint) than didplacebo-treated patients (14%; P<0.0001).32 In thesecond study, patients were randomized tomethylnaltrexone 0.15 mg/kg or placebo with thosein the methylnaltrexone group allowed to increasethe dose to 0.30 mg/kg if the patient had 2 or fewerrescue-free laxations up to day 8. Methylnaltrexonewas superior to placebo for both primary endpoints:the proportion of patients with a rescue-free laxationwithin 4 hours of the first dose (48% vs 16%;P<0.0001) and the proportion of patients with arescue-free laxation within 4 hours after at least 2 ofthe first 4 doses of study medication (52% vs 8%;P<0.0001).33 In both clinical trials, there was noapparent interference with the central analgesiceffects of the opioid with no clinically relevantchanges in pain scores from baseline in eithertreatment groups.

The most common adverse events in the Phase 3trials compared with placebo were abdominal pain(28.5% vs 9.8%), flatulence (13.3% vs 5.7%), nausea(11.5% vs 4.9%), dizziness (7.3% vs 2.4%), diarrhea(5.5% vs 2.4%), and hyperhidrosis (6.7% vs 6.5%).34

Naloxegol is an oral PAMORA approved for thetreatment of OIC. Two identical Phase 3, double-blind trials evaluated naloxegol 12.5 or 25 mg versusplacebo administered once daily in the treatment ofoutpatients with non-cancer pain and OIC (N=652and N=700).35 The primary endpoint was theresponse rate at 12 weeks, defined as ≥3spontaneous BMs per week and an increase frombaseline of ≥1 spontaneous BM for ≥9 of 12 weeksand for ≥3 of the final 4 weeks. Results revealed thatnaloxegol 25 mg was associated with significantlyhigher responses rates among the intent-to-treatpopulation in both studies (44.4% vs 29.4%; P=0.001and 39.7% vs 29.3%; P=0.02). Among those with an

inadequate response to laxatives, response rateswere 48.7% vs 28.8%; P=0.002 and 46.8% vs 31.4%;P=0.01. The 12.5 mg dose was also associated with asignificantly higher response rate in one studyamong both the intent-to-treat population (40.8% vs29.4%; P=0.02) and those with inadequate responseto laxatives (42.6% vs 28.8%; P=0.03).35 Both doses ofnaloxegol were also associated with significantlygreater improvement versus placebo in somesecondary endpoints including a shorter time to thefirst post-dose spontaneous BM and a higher meannumber of days per week with ≥1 spontaneous BM.The efficacy of naloxegol was achieved without theloss of pain control. Pain scores and daily opioiddoses were similar with all treatment groups.35

The most common adverse events associated withnaloxegol are gastrointestinal events. In one of thePhase 3 trials, adverse events occurring significantlymore frequently versus placebo included abdominalpain (17.8% vs 3.3%), diarrhea (12.9% vs 5.9%),nausea (9.4% vs 4.1%), headache (9.0% vs 4.8%),flatulence (6.9% vs 1.1%), and upper abdominal pain(5.1% vs 1.1%).35 Adverse events tended to be morefrequent with the higher (25 mg) dose of naloxegolbut most events occurred early in the course oftreatment, were mild to moderate in intensity, andresolved during or after discontinuation of treatment.35

Other Agents: Prucalopride, Linaclotide

Prucalopride is a selective serotonin receptor type 4(5-HT4) agonist with enterokinetic activity that is notapproved in the US but is available in Europe,Canada and parts of Asia.17 The efficacy ofprucalopride 2 mg or 4 mg for the treatment of OICwas evaluated in a Phase 2 placebo-controlled trialinvolving 196 non-cancer patients.36 Response(defined as an increase from baseline of ≥1 completespontaneous BM per week averaged over 4 weeks)was higher in the prucalopride 2 mg and 4 mg groups(35.9% and 40.3%, respectively) compared to thosereceiving placebo (23.4%); although the difference wasonly statistically significant during the first week.36



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Linaclotide is a guanylate cyclase-C agonistindicated for irritable bowel syndrome withconstipation and chronic idiopathic constipation.The drug acts by increasing stool water content andtransit; thereby increasing bowel movementfrequency and loosening stool consistency.37

Although there are no data yet on the efficacy of

linaclotide in OIC, a randomized placebo-controlledPhase 2 trial is currently underway to assesslinaclotide in adults receiving stable opioidtreatment for chronic non-cancer pain.38 The primaryendpoint is the change from baseline in the 8-weekspontaneous BM frequency rate.

Table 5. Targeted pharmacological agents for the treatment of OIC23,34,39

Drug Class Dose Indication Adverse EventsLubiprostone Chloride-2 channel 24 mcg twice daily orally OIC in patients with chronic, Nausea, diarrhea, abdominal pain(Amitiza®) activator non-cancer painMethylnaltrexone PAMORA Weight-based dosing, OIC in patients with advanced Abdominal pain, flatulence, nausea,(Relistor®) administered SC every illness receiving palliative care dizziness, diarrhea

other day, not to exceed after failing laxative therapy;1 dose/24 hours OIC in patients with chronic,

non-cancer pain Naloxegol PAMORA 12.5 or 25 mg/day orally OIC in patients with chronic, Abdominal pain, diarrhea, nausea, (Movantik®) non-cancer pain headache, flatulenceOIC = opioid-induced constipation; PAMORA = peripherally-acting μ-opioid receptor antagonist; SC = subcutaneous

Conclusions

OIC is a common and debilitating adverse eventassociated with chronic opioid therapy that isassociated with a substantial clinical and economicburden. While commonly used over-the-counterstool softeners and laxatives are generally effective;they do not address the underlyingpathophysiological mechanism. Good provider-patient communication and a proactive approachare important to prevent and treat OIC. Theavailability of new targeted therapies provides avaluable option for this difficult-to-treat condition.

Key Practice Points

• The use of opioids for chronic pain hasincreased dramatically in recent years

• OIC is a common side effect of opioids and isassociated with a variety of symptoms (eg,abdominal pain, cramping, bloating, hardstools, straining) that decrease patient qualityof life and can limit the use of these agents totreat pain

• Patients may be reluctant to discuss theirsituation and are generally not satisfied withthe results they receive from OTC products

• Laxatives do not address the mechanisms bywhich OIC occurs and are not approved totreat OIC

• New therapeutic targets and novel agents fortreating OIC are available

• OIC is a preventable adverse effect; thereforea proactive approach involving prophylacticlaxative regimens are important



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