ain is a significant and prevalent public health problem that costs society approximately $560 to $635 billion annually, an amount equal to about $2,000.00 for every person living in the US.1 As a result of the number of individuals experiencing persistent pain, the National Institute of Health reported that

approximately 200 million prescriptions for opioids were dispensed in 2013, a trend that has grown by more than 50% over the last 10 years, and by nearly 100% since 2000.2

Almost all patients requiring chronic opioid therapy develop side effects, the most common of which affect the gastrointestinal (GI) and central nervous systems (CNS).3,4

Although tolerance develops to many of the CNS side effects over time (ie, sedation), resolution of opioid-induced bowel dysfunction (OIBD), and more specifically opioid-induced constipation (OIC), does not occur with continued use.3

How prevalent is OIC? The numbers vary widely based on study design and patient populations. Based on an anal-ysis of 16 clinical trials and observational studies, OIC

FEATURE

P

Combating Opioid-Induced Constipation: New and Emerging TherapiesJeffrey Gudin, MDDirectorPain and Palliative CareEnglewood Hospital and Medical CenterEnglewood, New JerseyClinical Instructor of AnesthesiologyMt Sinai University School of MedicineNew York, New York

Adam Laitman, MDMedical GraduateXavier University School of Medicine, ArubaResearch AssociatePain and Palliative CareEnglewood Hospital and Medical CenterEnglewood, New Jersey

Jeffrey Fudin, BS, PharmD, FCCPClinical Pharmacy Specialist DirectorPGY2 Pain and Palliative Care Pharmacy ResidencyStratton VA Medical CenterAlbany, New York

Courtney Kominek, PharmD, BCPSClinical Pharmacy Specialist in Pain Management Harry S. Truman Memorial Veterans’ Hospital Columbia, Missouri

41November/December 2014 | Pract icalPainManagement.com

has been reported to occur in 15% to 90% of patients.5 When these stud-ies are qualified according to type of chronic pain, estimates from observa-tional studies in the United States sug-gested that the prevalence of OIC in patients with non-cancer pain ranged between 40% and 50%.6

In addition to being a common

side effect, OIC significantly affects a patient’s quality of life.7 A study of work productivity in patients on chronic opioid therapy found that OIC impacted productivity and activity levels. Specifically, the study found that patients reported 9% work time missed, 32% impairment while working (equivalent of 14 hours of

lost productivity per week), and 38% activity impairment.8 Additionally, participants in a recent OIC study commonly reported that their con-stipation interfered with the ability of their opioid medication to control pain, with 49% reporting moderate or complete interference, and 8% report-ing that they changed how they used their opioid in order to have a bowel movement.9

Effect of Opioids on GI TractMultiple mechanisms influence the occurrence of OIC. In fact, the very mechanisms that allow opioids to be effective pain medications are also involved in causing OIC. Opioid ago-nists mitigate pain by binding to opi-oid receptors that are located in the central and peripheral nervous sys-tems. Mu-opioid receptors, and to a lesser extent kappa- and delta-opioid receptors, are located throughout the GI tract. Here opioids reduce contrac-tility and tone leading to increased transit time.3 Specifically, they exert their effects in the neuronal plexi, located between the longitudinal and circular muscle layers (myenteric plexus) and within the submucosa (submucosal plexus),9 and indirectly through the central nervous system via intrathecal administration of opioids, decreasing GI motility and intestinal secretion.10

Passive absorption of fluids is increased and intestinal secretions are reduced in the GI tract with opi-oids due to increased frequency and strength of circular muscle contrac-tions that cause non-propulsive con-tractions.3 Within the myenteric plexus, opioids stimulate relaxation of the longitudinal smooth-muscle layer, thus increasing tonicity in the circu-lar smooth-muscle layer. The mecha-nism of this action is believed to occur through inhibition of acetylcholine release and inhibition of vasoactive

Table 1. Commonly Used Definition of Opioid-Induced Constipation Diagnosis of Opioid-Induced Constipation

1. Fewer than 3 bowel movements per week

2. Hard or lumpy stools

3. Sensation of incomplete evacuation

4. Sensation of anorectal obstruction

5. Straining with defecation

6. Bloating and abdominal pain relieved with bowel movements

7. Small stools

8. GERD (potentially)GERD, gastroesophageal reflux diseaseBased on references 11 and 17.

Table 2. Categories of Anti-constipatory Agents Category Mechanisms of Action

Bulk-producing Agents

Bulking agents work in both the small and large bowel, with an onset of action of 12 to 72 hours. They bulk up the stool so that it retains more water, making peristalsis easier. Examples include psyllium, methylcellulose, and dietary fiber.

Stool Softeners Stool softeners soften stool and make it “slippery,” making the stool easier to pass. These work in the colon and take from 6 to 8 hours to take effect.

Lubricants or Emollients Lubricants/emollients, such as mineral oil, soften and coat the stool, thus preventing colonic water absorption. Vegetable-oil enemas act as lubricants.

Hydrating Agents

Hydrating agents increase the water content in the stool, which makes the stool softer and easier to pass. Some of these work by increasing the bowel lumen osmolality. Examples include Fleet phospho-soda and Miralax.

StimulantsStimulants stimulate colonic contractions that propel stools foward. These agents irritate the lining of the intestines. Examples include cascara sagrada, bisacodyl, and senna.

Others

Prostaglandins, prokinetic drugs, and other agents change the way the intestine absorbs water and electrolytes, and increase the weight and frequency of stools while reducing transit time.

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intestinal peptide and nitric oxide release. Ultimately, this results in an increase in segmental contraction, while peristaltic activity is decreased, inducing constipation. 6 Reduced pro-pulsive contractions of longitudinal muscles also contributes to hard and dry stools.4 Rectal stool evacuation is decreased by an increased thresh-old for triggering of the anorectal reflex.3,11

Diagnosis of OICOpioids affect the entire gut, from the mouth to the anus, and OIBD refers to the constellation of GI effects.4 This includes gastroparesis, gastroesopha-geal reflux disease (GERD), and other GI-related disorders.12 Although no delineation for constipation has been universally accepted, various defini-tions of constipation exist.3,11,13,14 According to the American College of Gastroenterology definition, con-stipation is defined as unsatisfactory defecation with infrequent bowel movements, difficult stool passage, or both.11,15 Functional constipation, as outlined by the Rome III crite-ria, requires 2 or more of the follow-ing symptoms to occur no less than 25% of the time in the past 12 weeks: straining with bowel movements, passing lumpy or hard stools; feeling of incomplete evacuation; feeling of anorectal obstruction; using manual maneuvers for facilitation of defecation; and having less than 3 bowel move-ments per week.16 Even though this definition is not restricted to opioid- induced constipation, the Rome III criteria is often used to describe this condition (Table 1).11,17

Treatment OptionsOver-the-counter options for manage-ment of constipation include increas-ing dietary fiber intake, increasing fluid intake, and increasing physical activity.3 However, there is inadequate

evidence to support the use of these interventions for OIC, and they often are ineffective, which necessitates use of laxatives.3 Stimulant laxatives are often used first-line due to their low cost and efficacy despite not correcting the underlying mechanism.3,13 Table 2 describes categories of anti-constipat-ing agents.

Stimulant laxatives, including senna and bisacodyl, work by increasing mus-cle contractions. Patients, however, may develop tolerance and dependence to stimulant laxatives.3 Docusate, a sur-factant stool softener, does not assist with muscle contractility but is non-habit forming.3 Bulk-forming laxa-tives, for example psyllium, may lead to increased abdominal pain and bowel obstruction.3 Lactulose and polyeth-ylene glycol are osmotic laxatives that pull water into the GI tract and have evidence for use in OIC, but they do not target the actual OIC cause, and they may provoke electrolyte

abnormalities.3,11,13,15 Unfortunately, patients may have inadequate symp-tom relief from OIC with these laxa-tives alone or combined.

Pharmaceutical TherapyIt is not often in medicine that a phar-macological antidote exists to a drug treatment or adverse effect. Although newer select agents (ie, ion channel activators) have been approved for OIC, there is only one class of drug that targets the specific underlying cause of OIC—binding of opioids to the mu-receptors in the enteric ner-vous system. This new class, known as PAMORAs (Peripheral Acting Mu Opioid Receptor Antagonists), work by selectively inhibiting opioid recep-tors in the gut, thereby decreasing the constipating effects of opioids with-out affecting opioid-mediated analgesic effects within the central nervous sys-tem or precipitating withdrawal symp-toms (Table 3).4,18

Table 3. Current and Emerging Treatments for Opioid-Induced Constipation

Agent (Brand) Company Status

PAMORAs

Alvimopan (Entereg)GlaxoSmithKline FDA approved for postoperative

ileus; results in OIC were equivocal

Axelopran (formerly TD 1211)

Theravance, Inc. In Phase 3 clinical trials

Bevenopran Cubist Pharmaceuticals

In Phase 3 clinical trials

Methylnaltrexone (Relistor)

Salix Pharmaceuticals FDA approved for OIC in advanced illness in palliative care and CNCP

Naldemedine (S-297995) Shionogi Inc. In Phase 3 clinical trials

Naloxegol (Movantik) AstraZeneca FDA approved for OIC in CNCP

Chloride Channel Activator

Lubiprostone (Amitiza) Sucampo/Takeda FDA approved for OIC in CNCP

CNCP, chronic non-cancer pain; OIC, opioid-induced constipation; PAMORA, peripheral acting mu opioid receptor antagonists

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AlvimopanThe first available medication in this class was alvimopan (Entereg), which is indicated to accelerate the time to upper and lower gastrointestinal recov-ery following surgeries that include partial bowel resection with primary anastomosis.19

Although not specifically approved for OIC, alvimopan has been studied in 522 patients with OIC.20 The patients, who were all receiving 30 mg per day of morphine equivalent, were randomly assigned to receive oral alvimopan at three doses (0.5 mg twice daily, 1 mg once daily, 1 mg twice daily), or placebo for 6 weeks. When compared with pla-cebo, alvimopan significantly increased the mean weekly frequency of sponta-neous bowel movements (SBM) over the initial 3 weeks of treatment: 0.5 mg twice daily (+1.71 mean SBMs per week), 1 mg once daily (+1.64), and 1 mg twice daily (+2.52) (P < 0.001 for all comparisons). The increased fre-quency of SBMs and additional treat-ment effects (less straining, incomplete evacuation, abdominal bloating or dis-comfort; more stool consistency; and better appetite) were sustained for more than 6 weeks.20

In a study employing alvimopan (0.5 mg twice daily) for patients with chronic non-cancer pain (CNCP) on opioids, almovipan was associated with an increased risk of myocardial infarction compared to placebo, lead-ing to the issuance of a boxed warn-ing and REMS program.19 The man-ufacturer requires hospitals to enroll in the E.A.S.E. program to be able to acquire alvimopan. A hospital in the E.A.S.E. program must acknowledge the following:

• Hospital staff who prescribe, dis-pense, or administer the prod-uct have been provided the edu-cational materials on the need to limit the use to short-term, inpa-tient use.

• Patients will not receive more than 15 doses.

• The product will not be dispensed to patients after they have been dis-charged from the hospital.13

Methylnaltrexone BromideThe next PAMORA introduced to the market was methylnaltrexone bromide (Relistor). In 2010, methylnaltrex-one subcutaneous injection was FDA approved for the treatment of OIC in patients with advanced illness receiving palliative care. More recently, the agent was also approved for the treatment of OIC in adult patients with CNCP.21 Methylnaltrexone bromide is a qua-ternary amine with limited penetra-tion through the blood-brain barrier.

The clinical trials leading to meth-ylnaltrexone’s approval found that the agent produced reliable relief of constipation in opioid-treated pain patients—59% of patients receiving methylnaltrexone (12 mg subcutane-ous injection daily for 4 weeks) had more than 3 SBMs per week com-pared to 38% in the placebo treatment group.22 The most common side effects are abdominal pain, nausea, and vom-iting. Furthermore, methylnaltrexone did not appear to reverse the opioid’s analgesic effect or cause opioid with-drawal symptoms.21

In addition, significantly more meth-ylnaltrexone-treated patients had a bowel movement within 4 hours than did placebo-treated patients (52% vs. 9%; P < 0.0001). In approximately 30% of treated patients, laxation was reported within 30 minutes of a dose of methlynaltrexone. Two open-label extension studies suggested the laxation response appeared to be maintained over the course of 3 to 4 months.22

According to the Prescribing Information, methylnaltrexone is available in single use vials and sin-gle use pre-filled syringes. The dosage for CNCP is 12 mg, similar to those

patients with OIC in advanced illness weighing 62-114 kg; patients weighing 38-62 kg should receive 8 mg. Outside of this range, dosing is recommended at 0.15 mg/kg. Administration for CNCP is daily, with the caveat to discontinue all maintenance laxative therapy prior to starting injections; laxative(s) can be used as needed if there is a subopti-mal response to the agent after 3 days. Dosage reduction is recommended for patients with severe renal impairment.21

NaloxegolRecently, the FDA approved the first orally administered, once-daily PAMORA for OIC in patients with CNCP. Naloxegol (Movantik) is poly-ethylene glycol (PEG)ylated form of naloxone, and as a result of its chemical nature, it is not appreciably absorbed via the GI tract. It is expected to be available in the first half of 2015.23

The efficacy of naloxegol was studied in over 1300 patients who had been on oral opioids for an average of 3.6 years. OIC was defined as less than 3 SBMs per week with hard/lumpy stools, straining, or sensation of incom-plete evacuation or obstruction in 25% or more bowel movements in the last 4 weeks. Patients were randomly assigned to 3 treatment arms: nalox-egol 25 mg daily, naloxegol 12.5 mg daily, or placebo daily for 12 weeks. During the study, no other bowel reg-imens were permitted, but bisacodyl was allowed as rescue medication if patients did not have a bowel move-ment in 3 days.24

Two identical efficacy and safety studies were performed (Study 1 and Study 2). The primary endpoint was defined as ≥3 SBMs per week and a change from baseline of ≥1 SBM per week for at least 9 out of the 12 study weeks, and 3 out of the last 4 weeks.23

There was a statistically significant dif-ference in response for the 25 mg nal-oxegol treatment group versus placebo

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for the primary endpoint in Study 1 and Study 2. Statistical significance for the 12.5 mg treatment group versus placebo was observed in Study 1 but not in Study 2.23

One secondary endpoint in both studies was response in laxative users with OIC symptoms. In this subgroup, 42% and 50%, respectively, reported using laxatives on a daily basis. A statis-tically significantly higher percentage of patients in both studies responded with naloxegol 25 mg versus placebo. This was also seen with naloxegol 12.5 mg in Study 1; but was not tested in Study 2.

Time to first bowel movement was 6 to 20 hours in naloxegol-treated patients compared to 36 hours in the placebo group. The most com-mon adverse events were abdom-inal pain (12%-21%), diarrhea (6%-9%), nausea, and flatulence.24

Contraindications for naloxegol include known, suspected, or at increased risk of GI obstruction; con-comitant administration of strong cyto-chrome P (CYP) 450 3A4 inhibitors; and serious or severe hypersensitiv-ity reaction to naloxegol or any of its ingredients.24

Prior to initiation of naloxegol, it is recommended to discontinue all main-tenance laxative therapy, which can be resumed after 3 days if there is a subop-timal response to naloxegol. Standard dosing of naloxegol is 25 mg by mouth once daily 1 hour before or 2 hours following the first meal of the day. In patients unable to tolerate this dose, a 12.5 mg dose of naloxegol is recom-mended. Renal adjustment of the start-ing dose is suggested in patients with a creatinine clearance <60 mL/min.24

Serious adverse reactions that may occur include opioid withdrawal. Opioid withdrawal, considered in this trial to be at least 3 symptoms potentially related to opioid with-drawal, occurred in 1% of patients on naloxegol 12.5 mg compared to 3%

on naloxegol 25 mg; less than 1% of patients on placebo experienced opi-oid withdrawal (see Sidebar, page 46).

Emerging TherapiesWhile the most commonly used PAMORA on the market is methyl-

naltrexone, a variety of other PAMORA medications are in current clinical trials with anticipated results in 2015 and 2016. There are also a number of emerging PAMORA’s in development.

AxelopranAxelopran (formerly TD 1211) is an oral, once-daily peripherally selec-tive, multivalent inhibitor of the

mu-opioid receptor.25 It success-fully completed a Phase 2b study that demonstrated a sustained increase in bowel movement frequency in patients regardless of duration of OIC.26 As of September 2014, Phase 3 studies were pending.

BevenopranAnother emerging PAMORA cur-rently in Phase 3 of development is bevenopran (CB-5945; f/k/a ADL-5945). The latest trial planned is a multicenter, double-blind, placebo- controlled, parallel-group study in sub-jects with OIC taking opioid therapy for CNCP. Patients will be random-ized to receive either oral 0.25 mg bev-enopran twice daily or placebo for the

Multiple mechanisms cause opioid-induced

constipation (OIC). In fact, the very

mechanisms that allow opioids to be effective

are also involved in causing OIC.

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s of press time, the Drug Enforcement Agency (DEA) has designated naloxegol (Movantik) as a scheduled II controlled substance. Naloxegol was recently approved for the treatment of opioid-induced constipation and is part of a class of medications known as PAMORAs (Peripherally Acting Mu Opioid Receptor

Antagonists). Other FDA agents in this category include alvi-mopan (Entereg) and methylnaltrexone (Relistor).

This action was taken specifically due to naloxegol’s struc-tural resemblance to noroxymorphone.1-3 The abuse and dependence potential of the agent have been evaluated in clinical studies, and the company has submitted a petition to decontrol this medication.3 According to the labeling, nalox-egol has no risk of abuse or dependence.1

The DEA’s decision to schedule naloxegol in any category is disillusioned at best, and in the authors’ opinion, more likely a knee-jerk reaction to the recent high scrutiny attrib-utable to the purported “opioid epidemic.” By comparison, consider that naloxone is a legend but non-scheduled drug and dextromethorphan is an over-the-counter non-scheduled drug—both are dehydroxylated phenanthrenes. Also consider that more and more states are allowing naloxone in various packaging to be dispensed without a prescription and that naloxegol is a PEGylated form of naloxone.

Buprenorphine is a partial agonist/antagonist dehydrox-ylated phenantherene that is schedule III but certainly does have analgesic efficacy. But perhaps most telling is that noroxy-morphone has no analgesic or euphoric activity by the oral or IV routes, although admittedly does have agonist activ-ity by intrathecal administration according to animal stud-ies.4 Nevertheless, noroxymorphone is not naloxegol, and if injected intrathecally by a substance abuser (which is incom-prehensible and not studied), it would theoretically have opi-oid antagonist properties, not agonist activity. For all of these reasons, the authors are not convinced that there are any valid reasons to schedule naloxegol.

As noted, naloxegol is a PEGylated offshoot of naloxone, which limits its permeability across the blood brain barrier and into the central nervous system (CNS). This negligible penetration into the CNS prevents naloxegol from affecting

opioid analgesia occurring centrally. High-fat meals have been shown to increase the extent and rate of absorption, explaining the administration recommendation of taking naloxegol on an empty stomach. The volume of distribution ranged from 968 to 2140 L with low plasma protein binding. Naloxegol undergoes metabolism through the CYP3A4 system and is a substrate for p-glycoprotein (pGP); it is excreted primarily as metabolites via the feces (8%).1 It is worth noting that the PEGylation is most probably the reason for pGP absorption dependence across the GI tissue and the blood brain barrier, as naloxone does not share this pharmacokinetic characteris-tic. Because of this property, we can expect theoretically that pGP inducers such as rifampin could significantly increase naloxegol levels within the GI tract and also reduce serum blood levels. On the other hand, pGP inhibitors such as tela-previr could theoretically decrease naloxegol concentrations in the gut and increase blood levels. In the authors’ experience, such interactions are not generally recognized by community or institutional pharmacy computer software and should be considered if a patient has an unusual response to naloxegol.

Based on drug interaction studies, naloxegol is not expected to alter the clearance of drugs metabolized by CYP enzymes. However, naloxegol clearance may be affected by CYP3A4 inhibitors and inducers. It is recommended to avoid the con-comitant use of naloxegol with strong CYP3A4 inhibitors and inducers, as well as to avoid the consumption of grape-fruit juice or other natural products/vitamin supplements that could inhibit this enzyme. If unable to avoid moderate CYP3A4 inhibitors with naloxegol, it is advised to reduce the dose of naloxegol to 12.5 mg daily.1

References

1. Movantik package insert. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2014 Sept.

2. Movantik (naloxegol) Tablets C-II. https://www.movantikhcp.com. Accessed November 12, 2014.

3. FDA approves MOVANTIK (naloxegol Tablets C-II for the treatment of opioid- induced constipation in adult patients with chronic non-cancer pain. http://www.astrazeneca-us.com/media/press-releases/Article/20140916-fda-ap-proves-movantik-naloxegol-tablets-cii. Accessed November 12, 2014.

4. Lemberg KK, Siiskonen AO, Kontinen VK, Yli-Kauhaluoma JT, Kalso EA. Phar-macological characterization of noroxymorphone as a new opioid for spinal analgesia. Anest Analg. 2008;106:463-470.

Side Bar:

Jeffrey Fudin, BS, PharmD, FCCPClinical Pharmacy Specialist DirectorPGY2 Pain and Palliative Care Pharmacy ResidencyStratton VA Medical CenterAlbany, New York

Courtney Kominek, PharmD, BCPSClinical Pharmacy Specialist in Pain Management Harry S. Truman Memorial Veterans’ Hospital Columbia, Missouri

DEA Designates Naloxegol as Schedule II Drug

A

46 PracticalPainManagement.com | November/December 2014

12-week treatment period, followed by a 4-week follow-up period. According to Avarex Web site, “all subjects will be followed for 16 weeks regardless of when they discontinue study medica-tion.”27 The primary outcome measure is overall SBM rates over the 12-week double-blind treatment period.

NaldemedineAnother emerging PAMORA currently in Phase 3 of development is naldeme-dine (S-297995). The agent will be stud-ied in a double-blind, placebo-controlled multicenter study. The study will evalu-ate the efficacy and safety of naldemedine (0.3 mg once-daily) compared with pla-cebo for the treatment of OIC in CNCP patients on chronic opioid therapy. According to Shionogi’s website, nalde-medine “may prove more favorable than existing treatments, given its efficacy at lower doses in alleviating not just opioid- induced constipation but also nausea and vomiting.”28

Following a successful Phase 2 study completed in 2011, in which 75 subjects were randomized to 1 of 6 S-297995 cohorts (0.01 mg, 0.03 mg, 0.1 mg, 0.3 mg, 1.0 mg, or 3.0 mg), results demonstrated a statistically sig-nificant and dose-dependent increase from baseline in the number of SBMs at 24 hours post-dose, starting at doses of 0.3 mg. There was no evidence of opioid withdrawal and there was no impact on the analgesic effect of the opioids or a change in pupil size.29

Cardiovascular Risk In June 2014, a majority of FDA com-mittee members voted that the FDA should not require cardiovascular outcomes trials for PAMORAs being developed for the treatment of OIC in patients with CNCP. Following a clarification of the vote, the majority of the committee members suggested continued post-approval data collection for cardiovascular safety.30

ConclusionOIC is the most common adverse effect of chronic opioid therapy. It occurs as a natural response to opi-oid binding at mu receptors through-out the GI tract. Non-pharmacological strategies and laxatives are commonly employed to combat OIC; however, these strategies often fall short in effi-cacy. To avoid constipation resistant to laxative treatment, patients may decrease their use of opioids, which can lead to additional pain. For those failing first-line options, PAMORAs represent a reliable treatment option that targets the underlying cause of OIC. The emergence of this new class of agents has provided an opportunity for patients to receive effective pain relief while minimizing the unwanted peripheral effects of opioids.

Clinicians need to understand the indications, limitations, and contrain-dications—especially in patients with suspected bowel obstruction due to the risk of perforation.

Authors’ Bios: Jeffrey Gudin, MD, is Director of Pain and Palliative Care at Englewood Hospital and Medical Center in New Jersey, an affiliate of the Icahn School of Medicine at Mt Sinai. He is also clinical instructor of anesthesiology at Mt Sinai.

Dr. Gudin completed his residency in anesthesiology and a fellowship in pain medicine at the Yale University School of Medicine, in New Haven, Connecticut, where he was actively involved in research and teaching. Dr. Gudin is board certi-fied in Pain Medicine, Anesthesiology, Addiction Medicine and Hospice and Palliative Medicine. Dr. Gudin is an active speaker in the field of pain man-agement. His clinical and research focus includes pain management, opioid abuse and potential solutions, and increasing

clinician awareness of pain assessment and risk management. Dr. Gudin is on the Editorial Board of Practical Pain Management.

Adam Laitman, MD, completed his medical training at Xavier University School of Medicine, which is based in Aruba. His current interests of study include primary care along with pain and palliative management, and works as a research associate in Pain and Palliative Care at Englewood Hospital and Medical Center in New Jersey, an affiliate of the Icahn School of Medicine at Mt Sinai.

Jeffrey Fudin, BS, PharmD, FCCP, is Adjunct Associate Professor of Pharmacy Practice & Pain Management, Western New England University College of Pharmacy, in Springfield, Massachusetts, He also is Adjunct Assistant Professor of Pharmacy Practice, University of Connecticut School of Pharmacy, in Storrs, Connecticut, and Clinical Pharmacy Specialist and Director, PGY2 Pain & Palliative Care Pharmacy Residency at the Stratton VA Medical Center, in Albany, New York.

Dr. Fudin graduated from the Albany College of Pharmacy & Health Sciences (ACPHS) with his Bachelors Degree and his PharmD. He was awarded and completed an American Cancer Society Sponsored Fellowship in Oncology/Hematology at SUNY/Upstate Medical Center shortly after his undergraduate work. He is a Diplomate of the American Academy of Pain Management, a Fellow of the American College of Clinical Pharmacy (ACCP), and a member of several other professional organizations. Dr. Fudin is a Section Editor for Pain Medicine and is on the Editorial Board of Practical Pain Management. He is Founder/Chairman of Professionals for Rational Opioid Monitoring & Pharmacotherapy (PROMPT), an advo-cacy group in favor of safe opioid pre-scribing by encouraging clinician edu-cation, proactive risk stratification, and appropriate therapeutic monitoring.

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8. Coyne KS, LoCasale RJ, Datto CJ, Sexton CC, Yeomans K, Tack J. Opioid-induced constipation in patients with chronic noncancer pain in the USA, Canada, Germany, and the UK: descriptive analysis of baseline patient-reported outcomes and retrospective chart review. Clinicoecon Outcomes Res. 2014;6:269-281.

9. Sprawls KS, Spierings ELH, Tran D. Drugs in development for opioid-induced constipation. http://cdn.intechopen.com/pdfs-wm/31222.pdf. Accessed November 25, 2014.

10. Anderson, V. & Burchiel, K as cited in Ruan, Xiulu. Drug-Related Side Effects of Long Term Intrathecal Morphine Thaerpy. Pain Physician. 2007;10:357-365.

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bowel dysfunction: epidemiology, pathophysiol-ogy, diagnosis, and initial therapeutic manage-ment. Am J Gastroenterol Suppl. 2014;2:31-37.

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15. Brandt LW, Prather CM, Quigley EMM, Schiller LR, Schoeneld P, Talley NH. Systematic review on the management of chronic constipation in North America. Am J Gastroenterol. 2005;100(1)S5-S22.

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Courtney Kominek, PharmD, BCPS, completed her Doctor of Pharmacy at the University of Pittsburgh, School of Pharmacy. She completed a PGY-1 Pharmacy Practice Residency at the Dayton Veterans Affairs Medical Center in Dayton, OH, and a PGY-2 Pain Management and Palliative Care Pharmacy Residency at the West Palm Beach Veterans Affairs Medical Center in West Palm Beach, FL. Currently, Dr. Kominek is a Clinical Pharmacy

Specialist in Pain Management at the Harry S. Truman Memorial Veterans’ Hospital in Columbia, Missouri.

Dr. Gudin has disclosed that he receives consultant fees from Alere, INSYS, XenoPort, Zogenix, and Necktar. He also receives speaker bureau fees from AstraZeneca, Teva, Iroka, Salix, Purdue, Depomed, XenoPort, and Mallinckrodt.

Dr. Fudin has disclosed that he receives consultant fees from Millennium Health and Zogenix. He also receives

speaker bureau fees from AstraZeneca and Millennium Health.

Dr. Kominek and Dr. Laitman have no financial conflicts to disclose.

Drs. Fudin and Kominek disclosed that their involvement with this article was not prepared as part of their official government duties as Clinical Pharmacy Specialists at the VA and stated opinions/assertions do not reflect the opinion of employers, employee affiliates, and/or pharmaceutical companies listed.

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Combating Opioid-Induced Constipat ion: New and Emerging Therapies

PracticalPainManagement.com | November/December 2014