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Combating -Induced : New and Emerging Therapies

Jeffrey Gudin, MD Jeffrey Fudin, BS, PharmD, FCCP Director Clinical Pharmacy Specialist Pain and Palliative Care Director Englewood Hospital and Medical Center PGY2 Pain and Palliative Care Pharmacy Residency Englewood, New Jersey Stratton VA Medical Center Clinical Instructor of Anesthesiology Albany, New York Mt Sinai University School of Medicine New York, New York Adam Laitman, MD Courtney Kominek, PharmD, BCPS Clinical Pharmacy Specialist in Pain Management Medical Graduate Harry S. Truman Memorial Veterans’ Hospital Xavier University School of Medicine, Aruba Columbia, Missouri Research Associate Pain and Palliative Care Englewood Hospital and Medical Center Englewood, New Jersey

ain is a significant and prevalent public health Almost all patients requiring chronic opioid therapy problem that costs society approximately develop side effects, the most common of which affect the $560 to $635 billion annually, an amount gastrointestinal (GI) and central nervous systems (CNS).3,4 equal to about $2,000.00 for every person Although tolerance develops to many of the CNS side effects living in the US.1 As a result of the number over time (ie, sedation), resolution of opioid-induced bowel of individuals experiencing persistent pain, dysfunction (OIBD), and more specifically opioid-induced P the National Institute of Health reported that constipation (OIC), does not occur with continued use.3 approximately 200 million prescriptions for were How prevalent is OIC? The numbers vary widely based dispensed in 2013, a trend that has grown by more than on study design and patient populations. Based on an anal- 50% over the last 10 years, and by nearly 100% since 2000.2 ysis of 16 clinical trials and observational studies, OIC

November/December 2014 | PracticalPainManagement.com 41 Combating Opioid-Induced Constipation: New and Emerging Therapies

Table 1. Commonly Used Definition of Opioid-Induced Constipation lost productivity per week), and 38% activity impairment.8 Additionally, Diagnosis of Opioid-Induced Constipation participants in a recent OIC study 1. Fewer than 3 bowel movements per week commonly reported that their con- 2. Hard or lumpy stools stipation interfered with the ability 3. Sensation of incomplete evacuation of their opioid to control 4. Sensation of anorectal obstruction pain, with 49% reporting moderate or complete interference, and 8% report- 5. Straining with defecation ing that they changed how they used 6. Bloating and abdominal pain relieved with bowel movements their opioid in order to have a bowel 7. Small stools movement.9 8. GERD (potentially) Effect of Opioids on GI Tract GERD, gastroesophageal reflux disease Based on references 11 and 17. Multiple mechanisms influence the occurrence of OIC. In fact, the very Table 2. Categories of Anti-constipatory Agents mechanisms that allow opioids to be Category Mechanisms of Action effective pain are also involved in causing OIC. Opioid ago- Bulking agents work in both the small and large bowel, nists mitigate pain by binding to opi- with an onset of action of 12 to 72 hours. They bulk up Bulk-producing Agents the stool so that it retains more water, making peristalsis oid receptors that are located in the easier. Examples include , methylcellulose, and central and peripheral nervous sys- . tems. Mu-opioid receptors, and to a Stool softeners soften stool and make it “slippery,” making lesser extent kappa- and delta-opioid Stool Softeners the stool easier to pass. These work in the colon and take receptors, are located throughout the from 6 to 8 hours to take effect. GI tract. Here opioids reduce contrac- tility and tone leading to increased Lubricants/emollients, such as , soften and 3 Lubricants or Emollients coat the stool, thus preventing colonic water absorption. transit time. Specifically, they exert Vegetable-oil act as lubricants. their effects in the neuronal plexi, located between the longitudinal Hydrating agents increase the water content in the stool, which makes the stool softer and easier to pass. Some and circular muscle layers (myenteric Hydrating Agents of these work by increasing the bowel lumen osmolality. plexus) and within the submucosa Examples include Fleet phospho-soda and Miralax. (submucosal plexus),9 and indirectly through the central nervous system via Stimulants stimulate colonic contractions that propel stools Stimulants foward. These agents irritate the lining of the intestines. intrathecal administration of opioids, Examples include cascara sagrada, , and senna. decreasing GI motility and intestinal secretion.10 Prostaglandins, prokinetic , and other agents change the way the intestine absorbs water and electrolytes, and Passive absorption of fluids is Others increase the weight and frequency of stools while reducing increased and intestinal secretions transit time. are reduced in the GI tract with opi- oids due to increased frequency and strength of circular muscle contrac- has been reported to occur in 15% to side effect, OIC significantly affects tions that cause non-propulsive con- 90% of patients.5 When these stud- a patient’s quality of life.7 A study tractions.3 Within the myenteric ies are qualified according to type of of work productivity in patients on plexus, opioids stimulate relaxation of chronic pain, estimates from observa- chronic opioid therapy found that the longitudinal smooth-muscle layer, tional studies in the United States sug- OIC impacted productivity and thus increasing tonicity in the circu- gested that the prevalence of OIC in activity levels. Specifically, the study lar smooth-muscle layer. The mecha- patients with non-cancer pain ranged found that patients reported 9% work nism of this action is believed to occur between 40% and 50%.6 time missed, 32% impairment while through inhibition of acetylcholine In addition to being a common working (equivalent of 14 hours of release and inhibition of vasoactive

42 PracticalPainManagement.com | November/December 2014 Combating Opioid-Induced Constipation: New and Emerging Therapies

intestinal peptide and nitric oxide Table 3. Current and Emerging Treatments for Opioid-Induced Constipation release. Ultimately, this results in an increase in segmental contraction, Agent (Brand) Company Status while peristaltic activity is decreased, PAMORAs 6 inducing constipation. Reduced pro- GlaxoSmithKline FDA approved for postoperative pulsive contractions of longitudinal (Entereg) ileus; results in OIC were muscles also contributes to hard and equivocal 4 dry stools. Rectal stool evacuation Theravance, Inc. In Phase 3 clinical trials is decreased by an increased thresh- (formerly TD 1211) old for triggering of the anorectal Cubist In Phase 3 clinical trials 3,11 reflex. Pharmaceuticals Salix Pharmaceuticals FDA approved for OIC in Diagnosis of OIC advanced illness in palliative care (Relistor) Opioids affect the entire gut, from the and CNCP mouth to the anus, and OIBD refers to the constellation of GI effects.4 This (S-297995) Shionogi Inc. In Phase 3 clinical trials includes gastroparesis, gastroesopha- (Movantik) AstraZeneca FDA approved for OIC in CNCP geal reflux disease (GERD), and other Chloride Channel Activator GI-related disorders.12 Although no delineation for constipation has been (Amitiza) Sucampo/Takeda FDA approved for OIC in CNCP universally accepted, various defini- CNCP, chronic non-cancer pain; OIC, opioid-induced constipation; PAMORA, peripheral acting mu tions of constipation exist.3,11,13,14 antagonists According to the American College of Gastroenterology definition, con- stipation is defined as unsatisfactory defecation with infrequent bowel evidence to support the use of these abnormalities.3,11,13,15 Unfortunately, movements, difficult stool passage, interventions for OIC, and they often patients may have inadequate symp- or both.11,15 Functional constipation, are ineffective, which necessitates use tom relief from OIC with these laxa- as outlined by the Rome III crite- of .3 Stimulant laxatives are tives alone or combined. ria, requires 2 or more of the follow- often used first-line due to their low ing symptoms to occur no less than cost and efficacy despite not correcting Pharmaceutical Therapy 25% of the time in the past 12 weeks: the underlying mechanism.3,13 Table 2 It is not often in medicine that a phar- straining with bowel movements, describes categories of anti-constipat- macological antidote exists to a passing lumpy or hard stools; feeling ing agents. treatment or adverse effect. Although of incomplete evacuation; feeling of Stimulant laxatives, including senna newer select agents (ie, ion channel anorectal obstruction; using manual and bisacodyl, work by increasing mus- activators) have been approved for maneuvers for facilitation of defecation; cle contractions. Patients, however, may OIC, there is only one class of drug and having less than 3 bowel move- develop tolerance and dependence to that targets the specific underlying ments per week.16 Even though this stimulant laxatives.3 , a sur- cause of OIC—binding of opioids to definition is not restricted to opioid- factant stool softener, does not assist the mu-receptors in the enteric ner- induced constipation, the Rome III with muscle contractility but is non- vous system. This new class, known criteria is often used to describe this habit forming.3 Bulk-forming laxa- as PAMORAs (Peripheral Acting Mu condition (Table 1).11,17 tives, for example psyllium, may lead Opioid Receptor Antagonists), work to increased abdominal pain and bowel by selectively inhibiting opioid recep- Treatment Options obstruction.3 and polyeth- tors in the gut, thereby decreasing the Over-the-counter options for manage- ylene glycol are osmotic laxatives that constipating effects of opioids with- ment of constipation include increas- pull water into the GI tract and have out affecting opioid-mediated ing dietary fiber intake, increasing evidence for use in OIC, but they effects within the central nervous sys- fluid intake, and increasing physical do not target the actual OIC cause, tem or precipitating withdrawal symp- activity.3 However, there is inadequate and they may provoke electrolyte toms (Table 3).4,18

November/December 2014 | PracticalPainManagement.com 43 Combating Opioid-Induced Constipation: New and Emerging Therapies

Alvimopan • Patients will not receive more than patients with OIC in advanced illness The first available medication in this 15 doses. weighing 62-114 kg; patients weighing class was alvimopan (Entereg), which • The product will not be dispensed 38-62 kg should receive 8 mg. Outside is indicated to accelerate the time to to patients after they have been dis- of this range, dosing is recommended at upper and lower gastrointestinal recov- charged from the hospital.13 0.15 mg/kg. Administration for CNCP ery following surgeries that include is daily, with the caveat to discontinue partial bowel resection with primary Methylnaltrexone Bromide all maintenance therapy prior anastomosis.19 The next PAMORA introduced to the to starting injections; laxative(s) can Although not specifically approved market was methylnaltrexone bromide be used as needed if there is a subopti- for OIC, alvimopan has been studied in (Relistor). In 2010, methylnaltrex- mal response to the agent after 3 days. 522 patients with OIC.20 The patients, one subcutaneous injection was FDA Dosage reduction is recommended for who were all receiving 30 mg per day of approved for the treatment of OIC in patients with severe renal impairment.21 equivalent, were randomly patients with advanced illness receiving assigned to receive oral alvimopan at palliative care. More recently, the agent Naloxegol three doses (0.5 mg twice daily, 1 mg was also approved for the treatment of Recently, the FDA approved the once daily, 1 mg twice daily), or placebo OIC in adult patients with CNCP.21 first orally administered, once-daily for 6 weeks. When compared with pla- Methylnaltrexone bromide is a qua- PAMORA for OIC in patients with cebo, alvimopan significantly increased ternary amine with limited penetra- CNCP. Naloxegol (Movantik) is poly- the mean weekly frequency of sponta- tion through the blood-brain barrier. ethylene glycol (PEG)ylated form of neous bowel movements (SBM) over The clinical trials leading to meth- , and as a result of its chemical the initial 3 weeks of treatment: 0.5 ylnaltrexone’s approval found that nature, it is not appreciably absorbed mg twice daily (+1.71 mean SBMs per the agent produced reliable relief of via the GI tract. It is expected to be week), 1 mg once daily (+1.64), and 1 constipation in opioid-treated pain available in the first half of 2015.23 mg twice daily (+2.52) (P < 0.001 for patients—59% of patients receiving The efficacy of naloxegol was studied all comparisons). The increased fre- methylnaltrexone (12 mg subcutane- in over 1300 patients who had been quency of SBMs and additional treat- ous injection daily for 4 weeks) had on oral opioids for an average of 3.6 ment effects (less straining, incomplete more than 3 SBMs per week com- years. OIC was defined as less than evacuation, abdominal bloating or dis- pared to 38% in the placebo treatment 3 SBMs per week with hard/lumpy comfort; more stool consistency; and group.22 The most common side effects stools, straining, or sensation of incom- better appetite) were sustained for more are abdominal pain, nausea, and vom- plete evacuation or obstruction in 25% than 6 weeks.20 iting. Furthermore, methylnaltrexone or more bowel movements in the last In a study employing alvimopan did not appear to reverse the opioid’s 4 weeks. Patients were randomly (0.5 mg twice daily) for patients with analgesic effect or cause opioid with- assigned to 3 treatment arms: nalox- chronic non-cancer pain (CNCP) on drawal symptoms.21 egol 25 mg daily, naloxegol 12.5 mg opioids, almovipan was associated In addition, significantly more meth- daily, or placebo daily for 12 weeks. with an increased risk of myocardial ylnaltrexone-treated patients had a During the study, no other bowel reg- infarction compared to placebo, lead- bowel movement within 4 hours than imens were permitted, but bisacodyl ing to the issuance of a boxed warn- did placebo-treated patients (52% vs. was allowed as rescue medication if ing and REMS program.19 The man- 9%; P < 0.0001). In approximately patients did not have a bowel move- ufacturer requires hospitals to enroll 30% of treated patients, laxation was ment in 3 days.24 in the E.A.S.E. program to be able to reported within 30 minutes of a dose Two identical efficacy and safety acquire alvimopan. A hospital in the of methlynaltrexone. Two open-label studies were performed (Study 1 and E.A.S.E. program must acknowledge extension studies suggested the laxation Study 2). The primary endpoint was the following: response appeared to be maintained defined as ≥3 SBMs per week and a • Hospital staff who prescribe, dis- over the course of 3 to 4 months.22 change from baseline of ≥1 SBM per pense, or administer the prod- According to the Prescribing week for at least 9 out of the 12 study uct have been provided the edu- Information, methylnaltrexone is weeks, and 3 out of the last 4 weeks.23 cational materials on the need to available in single use vials and sin- There was a statistically significant dif- limit the use to short-term, inpa- gle use pre-filled syringes. The dosage ference in response for the 25 mg nal- tient use. for CNCP is 12 mg, similar to those oxegol treatment group versus placebo

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for the primary endpoint in Study 1 on naloxegol 25 mg; less than 1% of mu-opioid receptor.25 It success- and Study 2. Statistical significance for patients on placebo experienced opi- fully completed a Phase 2b study that the 12.5 mg treatment group versus oid withdrawal (see Sidebar, page 46). demonstrated a sustained increase placebo was observed in Study 1 but in bowel movement frequency in not in Study 2.23 Emerging Therapies patients regardless of duration of One secondary endpoint in both While the most commonly used OIC.26 As of September 2014, Phase studies was response in laxative users PAMORA on the market is methyl- 3 studies were pending. 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 Multiple mechanisms was also seen with naloxegol 12.5 mg in Study 1; but was not tested in Study 2. Time to first bowel movement was cause opioid-induced 6 to 20 hours in naloxegol-treated patients compared to 36 hours in the placebo group. The most com- constipation (OIC). mon adverse events were abdom- inal pain (12%-21%), diarrhea (6%-9%), nausea, and flatulence.24 Contraindications for naloxegol In fact, the very include known, suspected, or at increased risk of GI obstruction; con- comitant administration of strong cyto- mechanisms that allow chrome P (CYP) 450 3A4 inhibitors; and serious or severe hypersensitiv- ity reaction to naloxegol or any of its opioids to be effective ingredients.24 Prior to initiation of naloxegol, it is recommended to discontinue all main- are also involved in 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 causing OIC. 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- , a variety of other Bevenopran mended. Renal adjustment of the start- PAMORA medications are in current Another emerging PAMORA cur- ing dose is suggested in patients with clinical trials with anticipated results rently in Phase 3 of development is a creatinine clearance <60 mL/min.24 in 2015 and 2016. There are also a bevenopran (CB-5945; f/k/a ADL- Serious adverse reactions that may number of emerging PAMORA’s in 5945). The latest trial planned is a occur include opioid withdrawal. development. multicenter, double-blind, placebo- Opioid withdrawal, considered in controlled, parallel-group study in sub- this trial to be at least 3 symptoms Axelopran jects with OIC taking opioid therapy potentially related to opioid with- Axelopran (formerly TD 1211) is an for CNCP. Patients will be random- drawal, occurred in 1% of patients on oral, once-daily peripherally selec- ized to receive either oral 0.25 mg bev- naloxegol 12.5 mg compared to 3% tive, multivalent inhibitor of the enopran twice daily or placebo for the

November/December 2014 | PracticalPainManagement.com 45 Side Bar: DEA Designates Naloxegol as Schedule II Drug Jeffrey Fudin, BS, PharmD, FCCP Courtney Kominek, PharmD, BCPS Clinical Pharmacy Specialist Clinical Pharmacy Specialist in Pain Management Director Harry S. Truman Memorial Veterans’ Hospital PGY2 Pain and Palliative Care Pharmacy Residency Columbia, Missouri Stratton VA Medical Center Albany, New York

s of press time, the Drug Enforcement Agency opioid analgesia occurring centrally. High-fat meals have been (DEA) has designated naloxegol (Movantik) as shown to increase the extent and rate of absorption, explaining a scheduled II controlled substance. Naloxegol the administration recommendation of taking naloxegol on was recently approved for the treatment of an empty stomach. The volume of distribution ranged from opioid-induced constipation and is part of 968 to 2140 L with low plasma protein binding. Naloxegol a class of medications known as PAMORAs undergoes metabolism through the CYP3A4 system and is A (Peripherally Acting Mu Opioid Receptor a substrate for p-glycoprotein (pGP); it is excreted primarily Antagonists). Other FDA agents in this category include alvi- as metabolites via the feces (8%).1 It is worth noting that the mopan (Entereg) and methylnaltrexone (Relistor). PEGylation is most probably the reason for pGP absorption This action was taken specifically due to naloxegol’s struc- dependence across the GI tissue and the blood brain barrier, tural resemblance to .1-3 The abuse and as naloxone does not share this pharmacokinetic characteris- dependence potential of the agent have been evaluated in tic. Because of this property, we can expect theoretically that clinical studies, and the company has submitted a petition to pGP inducers such as rifampin could significantly increase decontrol this medication.3 According to the labeling, nalox- naloxegol levels within the GI tract and also reduce serum egol has no risk of abuse or dependence.1 blood levels. On the other hand, pGP inhibitors such as tela- The DEA’s decision to schedule naloxegol in any category previr could theoretically decrease naloxegol concentrations in is disillusioned at best, and in the authors’ opinion, more the gut and increase blood levels. In the authors’ experience, likely a knee-jerk reaction to the recent high scrutiny attrib- such interactions are not generally recognized by community utable to the purported “opioid epidemic.” By comparison, or institutional pharmacy computer software and should be consider that naloxone is a legend but non-scheduled drug considered if a patient has an unusual response to naloxegol. and is an over-the-counter non-scheduled Based on drug interaction studies, naloxegol is not expected drug—both are dehydroxylated phenanthrenes. Also consider to alter the clearance of drugs metabolized by CYP enzymes. that more and more states are allowing naloxone in various However, naloxegol clearance may be affected by CYP3A4 packaging to be dispensed without a prescription and that inhibitors and inducers. It is recommended to avoid the con- naloxegol is a PEGylated form of naloxone. comitant use of naloxegol with strong CYP3A4 inhibitors is a partial agonist/antagonist dehydrox- and inducers, as well as to avoid the consumption of grape- ylated phenantherene that is schedule III but certainly does fruit juice or other natural products/vitamin supplements have analgesic efficacy. But perhaps most telling is that noroxy- that could inhibit this enzyme. If unable to avoid moderate morphone has no analgesic or euphoric activity by the oral CYP3A4 inhibitors with naloxegol, it is advised to reduce the or IV routes, although admittedly does have agonist activ- dose of naloxegol to 12.5 mg daily.1 ity by intrathecal administration according to animal stud- ies.4 Nevertheless, noroxymorphone is not naloxegol, and if References injected intrathecally by a substance abuser (which is incom- 1. Movantik package insert. Wilmington, DE: AstraZeneca Pharmaceuticals LP; prehensible and not studied), it would theoretically have opi- 2014 Sept. oid antagonist properties, not agonist activity. For all of these 2. Movantik (naloxegol) Tablets C-II. https://www.movantikhcp.com. Accessed November 12, 2014. reasons, the authors are not convinced that there are any valid 3. FDA approves MOVANTIK (naloxegol Tablets C-II for the treatment of opioid- reasons to schedule naloxegol. induced constipation in adult patients with chronic non-cancer pain. http:// As noted, naloxegol is a PEGylated offshoot of naloxone, www.astrazeneca-us.com/media/press-releases/Article/20140916-fda-ap- proves-movantik-naloxegol-tablets-cii. Accessed November 12, 2014. which limits its permeability across the blood brain barrier 4. Lemberg KK, Siiskonen AO, Kontinen VK, Yli-Kauhaluoma JT, Kalso EA. Phar- and into the central nervous system (CNS). This negligible macological characterization of noroxymorphone as a new opioid for spinal penetration into the CNS prevents naloxegol from affecting analgesia. Anest Analg. 2008;106:463-470.

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12-week treatment period, followed by clinician awareness of pain assessment a 4-week follow-up period. According and risk management. Dr. Gudin is on to Avarex Web site, “all subjects will Conclusion the Editorial Board of Practical Pain be followed for 16 weeks regardless of OIC is the most common adverse Management. when they discontinue study medica- effect of chronic opioid therapy. It Adam Laitman, MD, completed his tion.”27 The primary outcome measure occurs as a natural response to opi- medical training at Xavier University is overall SBM rates over the 12-week oid binding at mu receptors through- School of Medicine, which is based in double-blind treatment period. out the GI tract. Non-pharmacological Aruba. His current interests of study strategies and laxatives are commonly include primary care along with pain and Naldemedine employed to combat OIC; however, palliative management, and works as a Another emerging PAMORA currently these strategies often fall short in effi- research associate in Pain and Palliative in Phase 3 of development is naldeme- cacy. To avoid constipation resistant Care at Englewood Hospital and Medical dine (S-297995). The agent will be stud- to laxative treatment, patients may Center in New Jersey, an affiliate of the ied in a double-blind, placebo-controlled decrease their use of opioids, which Icahn School of Medicine at Mt Sinai. multicenter study. The study will evalu- can lead to additional pain. For those Jeffrey Fudin, BS, PharmD, FCCP, is ate the efficacy and safety of naldemedine failing first-line options, PAMORAs Adjunct Associate Professor of Pharmacy (0.3 mg once-daily) compared with pla- represent a reliable treatment option Practice & Pain Management, Western cebo for the treatment of OIC in CNCP that targets the underlying cause of New England University College of patients on chronic opioid therapy. OIC. The emergence of this new class Pharmacy, in Springfield, Massachusetts, According to Shionogi’s website, nalde- of agents has provided an opportunity He also is Adjunct Assistant Professor medine “may prove more favorable than for patients to receive effective pain of Pharmacy Practice, University of existing treatments, given its efficacy at relief while minimizing the unwanted Connecticut School of Pharmacy, in lower doses in alleviating not just opioid- peripheral effects of opioids. Storrs, Connecticut, and Clinical induced constipation but also nausea Clinicians need to understand the Pharmacy Specialist and Director, and vomiting.”28 indications, limitations, and contrain- PGY2 Pain & Palliative Care Pharmacy Following a successful Phase 2 dications—especially in patients with Residency at the Stratton VA Medical study completed in 2011, in which suspected bowel obstruction due to Center, in Albany, New York. 75 subjects were randomized to 1 of 6 the risk of perforation. Dr. Fudin graduated from the Albany S-297995 cohorts (0.01 mg, 0.03 mg, College of Pharmacy & Health Sciences 0.1 mg, 0.3 mg, 1.0 mg, or 3.0 mg), (ACPHS) with his Bachelors Degree results demonstrated a statistically sig- Authors’ Bios: Jeffrey Gudin, MD, is and his PharmD. He was awarded and nificant and dose-dependent increase Director of Pain and Palliative Care at completed an American Cancer Society from baseline in the number of SBMs Englewood Hospital and Medical Center Sponsored Fellowship in Oncology/ at 24 hours post-dose, starting at doses in New Jersey, an affiliate of the Icahn Hematology at SUNY/Upstate Medical of 0.3 mg. There was no evidence of School of Medicine at Mt Sinai. He is Center shortly after his undergraduate opioid withdrawal and there was no also clinical instructor of anesthesiology work. He is a Diplomate of the American impact on the analgesic effect of the at Mt Sinai. Academy of Pain Management, a Fellow opioids or a change in pupil size.29 Dr. Gudin completed his residency in of the American College of Clinical anesthesiology and a fellowship in pain Pharmacy (ACCP), and a member of Cardiovascular Risk medicine at the Yale University School of several other professional organizations. In June 2014, a majority of FDA com- Medicine, in New Haven, Connecticut, Dr. Fudin is a Section Editor for Pain mittee members voted that the FDA where he was actively involved in research Medicine and is on the Editorial Board should not require cardiovascular and teaching. Dr. Gudin is board certi- of Practical Pain Management. He is outcomes trials for PAMORAs being fied in Pain Medicine, Anesthesiology, Founder/Chairman of Professionals developed for the treatment of OIC Addiction Medicine and Hospice and for Rational Opioid Monitoring & in patients with CNCP. Following a Palliative Medicine. Dr. Gudin is an Pharmacotherapy (PROMPT), an advo- clarification of the vote, the majority active speaker in the field of pain man- cacy group in favor of safe opioid pre- of the committee members suggested agement. His clinical and research focus scribing by encouraging clinician edu- continued post-approval data collection includes pain management, opioid abuse cation, proactive risk stratification, and for cardiovascular safety.30 and potential solutions, and increasing appropriate therapeutic monitoring.

November/December 2014 | PracticalPainManagement.com 47 Combating Opioid-Induced Constipation: New and Emerging Therapies

Courtney Kominek, PharmD, BCPS, Specialist in Pain Management at the speaker bureau fees from AstraZeneca completed her Doctor of Pharmacy at Harry S. Truman Memorial Veterans’ and Millennium Health. the University of Pittsburgh, School Hospital in Columbia, Missouri. Dr. Kominek and Dr. Laitman have of Pharmacy. She completed a PGY-1 Dr. Gudin has disclosed that he receives no financial conflicts to disclose. Pharmacy Practice Residency at the consultant fees from Alere, INSYS, Drs. Fudin and Kominek disclosed Dayton Veterans Affairs Medical XenoPort, Zogenix, and Necktar. He that their involvement with this article Center in Dayton, OH, and a PGY-2 also receives speaker bureau fees from was not prepared as part of their official Pain Management and Palliative Care AstraZeneca, Teva, Iroka, Salix, Purdue, government duties as Clinical Pharmacy Pharmacy Residency at the West Palm Depomed, XenoPort, and Mallinckrodt. Specialists at the VA and stated opinions/ Beach Veterans Affairs Medical Center Dr. Fudin has disclosed that he assertions do not reflect the opinion of in West Palm Beach, FL. Currently, receives consultant fees from Millennium employers, employee affiliates, and/or Dr. Kominek is a Clinical Pharmacy Health and Zogenix. He also receives pharmaceutical companies listed.

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