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Exploring Relief and Managing Side Effects of This activity issupported byan educationalgrant from AstraZeneca. Sponsored by Global Education Group. MedLearning Group istheeducationpartner. EXPIRATION DATE RELEASE DATE: A CME/CESupplement to PWJ—PAINWeek Journal JOURNAL SUPPLEMENT December 1, 2014 : December 31, 2015 Faculty Program Overview Sanford M. Silverman, MD This case-based enduring activity will cover the personalized care of patients with Medical Director chronic pain. Comprehensive Pain Medicine Target Audience Pompano Beach, Florida This activity is designed to meet the educational needs of frontline clinicians who care for patients with chronic pain such as physicians, nurse practitioners, physician assistants, and pharmacists. Learning Objectives Upon completion of the program, attendees should be able to: - Discuss the different classes of used in the treatment of chronic pain, and their safety, efficacy and indications - Recognize the most common -induced side effects, OIC, and the impact of treatments on analgesia - Identify attitudes, barriers and facilitators to communicating with patients about their bowel habits - Identify treatments used for the management of OIC

Physician Accreditation Statement- Global Education Group is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Physician Credit Designation- Global Education Group designates this enduring activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Nursing Continuing Education- Global Education Group is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s COA. This educational activity for 1.0 contact hours is provided by Global Education Group. Nurses should claim only the credit commensurate with the extent of their participation in the activity. Pharmacist Accreditation Statement- Global Education Group (Global) is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Credit Designation- Global Education Group designates this continuing education activity for 1.0 contact hour(s) (0.1 CEUs) of the Accreditation Council for Pharmacy Education. (Universal Activity Number - 0530-9999-14-170-H01-P). This is a knowledge based activity. Nurse Practitioner Continuing Education- Global Education Group is approved as a provider of nurse practitioner continuing education by the American Association of Nurse Practitioners: AANP Provider Number 11021. This program has been approved for 0.25 contact hours of continuing education (1.0 Pharmacology hours). Physician Assistants - AAPA accepts certificates of participation for educational activities certified for AMA PRA Category 1 Credit™ from organizations accredited by ACCME or a recognized state medical society. Physician assistants may receive a maximum of 1.0 hours of Category 1 credit for completing this program.

1 Exploring Relief and Managing Side Effects of

Instructions to Receive Credit- There are no fees for participating and receiving CME credit for this enduring activity. To receive CME/CE credit participants must: - Read the learning objectives and faculty disclosures. - Complete the pre-test through this link: https://www.research.net/s/PainSupppre - Participate in the activity. - Complete the post-test and activity evaluation through this link: https://www.research.net/s/Painsupppost - Physicians who successfully complete the post-test and evaluation will receive CME credit. - All non-physician participants who successfully complete the post-test and evaluation will receive a certificate of participation. All certificates will be emailed within 30 days. Fee & Refund/Cancellation Policy- There is no fee for this educational activity. Disclosure of Conflicts of Interest-Global Education Group (Global) requires instructors, planners, managers and other individuals and their spouse/life partner who are in a position to control the content of this activity to disclose any real or apparent conflict of interest they may have as related to the content of this activity. All identified conflicts of interest are thoroughly vetted by Global for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations. The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: Name of Faculty or Presenter Reported Financial Relationship Sanford M. Silverman, MD Nothing to disclose The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: Name of Planner or Manager Reported Financial Relationship Ashley Marostica, RN, MSN Nothing to disclose Amanda Glazar, PhD Nothing to disclose Matthew Frese Nothing to disclose Andrea Funk Nothing to disclose Christina Gallo Nothing to disclose Melissa Johnson Nothing to disclose Cheryl Zigrand Nothing to disclose Disclosure of Unlabeled Use- This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Global Education Group (Global) does not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Disclaimer- Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, , or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

2 The PAINWeekEnd™ Educational Summit Series brings live education Hypogonadism and likely hypogonadotropic hypogonadism have about pain management to healthcare professionals through regional correlated with side effects in men such as sexual dysfunction, professional conferences. Each conference also includes an accredited depression, and decreased energy levels. Chronic opioid continuing medical education activity hosted by a faculty chairperson. administration can lead to decreases in testosterone in a dose- This supplement is designed to capture and expand upon some of the dependent manner. Women can also have hormonal side effects of content of the PAINWeekEnd™ live program in print form. The , such as depression, dysmenorrhea, sexual dysfunction, and management of chronic pain with opioids and the ensuing side reduced bone mineral density.4 effects will be discussed, with a particular focus on opioid-induced Hyperalgesia or hyperalgia is an increased sensitivity to pain that (OIC), and how to communicate with patients about presents as increased pain despite increasing doses of opioids. constipation. Long-term opioid use or use of high doses may be associated with the development of hyperalgesia, which may be related to opioid CHRONIC PAIN OVERVIEW metabolites and opioid-induced cell apoptosis.4 The Institute of Medicine has estimated that more than 100 million Americans are living with pain that lasts from weeks to years, and that OPIOID-INDUCED CONSTIPATION 1 the financial costs of chronic pain total up to $635 billion annually. Constipation is an extremely common side effect of opioid treatment, The high prevalence of chronic pain goes hand in hand with high rates occurring in 40% to 95% of patients, with the possibility of occurring of opioid therapy. Sales of opioid analgesics quadrupled between 1999 after just a single dose.5 And, with the increase in the use of opioids, and 2010, with more than 256 million opioid prescriptions filled in 2009 the absolute numbers of patients affected by OIC is also growing.8 2 alone. Opioid therapy is not without its side effects, though, and In patients who require chronic analgesia, constipation can be a clinicians must be aware of the common side effects and ready to debilitating side effect that negatively impacts quality of life.4,9 With up address them in a timely manner to prevent its toxicity from to 56% of patients discontinuing their opioid treatment due to lack of outweighing its effectiveness in treating pain. Of the side effects efficacy or side effects, addressing constipation is critical.3,10 commonly associated with opioid use, constipation is the most prevalent.3 Opioid-induced constipation (OIC) is an expected part of While OIC can occur in any patient treated with opioids, there are opioid treatment that is unlikely to improve over time, and so it should certain risk factors that can increase a patient’s likelihood of be closely monitored and treated prophylactically, with a bowel regimen developing OIC. These risk factors include advanced age, female, initiated as soon as it is deemed necessary.2,4,5 type of opioid therapy, relative immobility of the patient, dehydration, altered nutritional intake, anal fissures, and any kind of mechanical The American Society of Anesthesiologists Task Force on Chronic Pain obstruction within the .11,12 Also, based on the Management and the American Society of Regional Anesthesia and numerous causes of constipation, which can be either primary Pain Medicine joined forces to created practice guidelines for the (idiopathic) or secondary, it is important to determine if opioids are management of chronic pain. These guidelines recognize that many dif- actually the cause of the constipation so that the treatment plan is ferent classes of pharmacologic agents can be used to treat chronic pain, accurately informed (Table 1).13 including anticonvulsants, antidepressants, benzodiazepines, N-methyl-D-aspartate (NMDA) receptor antagonists, nonsteroidal Table 1. Examples of primary (idiopathic) and secondary causes of anti-inflammatory drugs (NSAIDs), opioids, skeletal muscle relaxants, constipation symptoms.13 and topical agents such as lidocaine, capsaicin, and .6 This SECONDARY range of medicines gives an idea of the heterogeneous nature of pain, as PRIMARY (Idiopathic) Inadequate diet well as its range of severity, duration, and causes. IBS-C Normal-transit constipation Dehydration OPIOID-INDUCED SIDE EFFECTS Slow-transit constipation Inadequate physical activity Opioid therapy can be an effective tool, especially initially, in the quest Defecatory or rectal to relieve patients’ chronic pain.7 It can be associated with a number of evacuation disorders: Use of certain medications: complications, however, that may limit its effectiveness, leading to • Pelvic floor dyssynergia • Aluminum-containing antacids early discontinuation, under-dosing, and inadequate analgesia. Some • Hirschsprung’s disease • Antispasmodics of the most common side effects found to be associated with opioid • Anismus • Antidepressants use include constipation, , vomiting, respiratory depression, • Paradoxical pelvic floor • Diuretics physical dependence, and sedation.4 Other issues that can arise with contraction • Anticonvulsants opioid therapy include pruritus, dizziness, tolerance, diversion, and • Functional rectosigmoid • Pain medications hyperalgesia.4,5 obstruction (especially ) Nausea occurs in approximately 25% of patients treated with opioids, • Spastic pelvic floor syndrome • Calcium-channel blockers and is usually transient, although treatment should be instituted if • Descending perineum syndrome • Nonsteroidal substantial nausea and vomiting occur. The central nervous system anti-inflammatory drugs effects of opioid therapy, such as sedation and decreased cognition, are Older age Pregnancy also usually transient, but treatment might be required to help cope with Mechanical obstructions: the undesirable effects. These adverse events seem to present at opioid • Colon cancer initiation or with dose increases. Pruritus with opioid use occurs in 2% to • Postsurgical abnormalities 10% of patients, but the likelihood increases if the opioid is administered Endocrine/metabolic disorders: by epidural or intraspinal injections.5 • Diabetes Tolerance, which is a loss of potency, leads to requirements for • Hypothyroidism dose increases with accompanying decreases in effectiveness • Hypercalcemia over time. There is no cross tolerance with opioids, so the development • Hyperparathyroidism of tolerance to one opioid does not necessarily confer tolerance to a • Hypokalemia different opioid. Therefore, switching opioids in a patient who has • Uremia developed tolerance may require lowering the dose of the second Neurologic conditions: opioid.4 • Cerebrovascular events Opioids have demonstrated effects on a number of hormones including • Multiple sclerosis testosterone, estrogen, luteinizing hormone, gonadotrophin releasing • Parkinson’s disease hormone, dehydroepiandrosterone, dehydroepiandrosterone , Psychological conditions: adrenocorticotropin, corticotropin-releasing hormone, and cortisol. • Depression • Anxiety

3 Clinician-Patient Communication Of the three receptor classes in the enteric nervous system – δ, κ, and Effective communication between the clinician and the patient about μ – the μ- seems to be the principal mediator of the constipation has been linked to improved outcomes, increased patient effects of opioid agonists on the gastrointestinal tract. The binding of satisfaction, and decreased utilization of care. This communication can opioid agonists to these receptors inhibits the release of excitatory and be strengthened by asking open-ended questions, actively listening inhibitory neurotransmitters, interrupting the contractions required to the patient, and displaying empathy during the patient’s visit.14 for intestinal motility and reducing mucosal secretions. Administering Because the topic of OIC deals with bowel habits that could be exogenous opioids can cause opioid bowel dysfunction by decreasing potentially embarrassing for the patient to discuss, it is important to peristalsis, reducing secretions into the gut, and increasing reabsorp- actively seek out the information from patients that might uncover tion of fluid from the gut, leading to the formation of dry, hard stools 19 symptoms that need to be addressed. Patients must feel that their that can be difficult to pass. clinician takes them seriously, or they may be reticent to admit to having symptoms.15 TREATING OPIOID-INDUCED CONSTIPATION When initiating an opioid regimen, it is safe to assume that all Both nonpharmacologic and pharmacologic treatment options patients treated with opioids will experience some degree of bowel are available for OIC. Its nonpharmacologic treatment is based on dysfunction during their treatment until proven otherwise. In order to lifestyle modification. Typically, these measures include increasing the properly assess whether OIC is an issue, an accurate medical history consumption of and fluids and increasing physical including current bowel habits and any current measures that may be activity, all of which should begin at the initiation of opioid therapy used to ensure regularity can help to establish a baseline. It would also and continue for the duration of treatment.20 According to the Agency be helpful to capture any history of bowel function variability that the for Healthcare Research and Quality (AHRQ) of the U.S Department of patient experienced either as an adult or a child. Health & Human Services, these changes in lifestyle should be One aspect to keep in mind when discussing OIC with patients is that implemented as soon as an individual is identified to be at risk for clinicians and patients may have vastly disparate definitions in mind constipation. Fluid intake should measure at least 1.5 liters (or 6 cups) regarding what constitutes constipation. The number of stools passed each day. Fiber provides the bulk needed by the colon to eliminate is just one of a number of criteria of constipation, and it is not even a body waste. As fiber passes through the colon, it acts as a sponge and necessary one for diagnosis, so if the correct questions are not asked, absorbs water, resulting in bulkier and softer stools. Then, waste moves patients who think they do not have constipation may actually have through the body more quickly, allowing for easier and more regular it by other parts of its definition. The components set forth by the Rome III criteria can offer up useful criteria to discuss with patients, bowel movements. For individuals whose fluid intake measures at least such as number of stools, straining, sensations while defecating, 1500 mL per day, a dietary fiber (including both insoluble and soluble and consistency of stools (Table 2), as can Table 3, which differentiates fiber) intake between 20 and 35 grams minimum per day is normal bowel characteristics from constipation symptoms.12,16 recommended. Activity recommendations should be tailored to each individual’s physical abilities and general level of health, and can vary Table 2. Rome III diagnostic criteria for constipation16 from walking 15 to 20 minutes or more once or twice a day for fully At least 2 of the following experienced for the last 3 months with mobile patients, to ambulating at least 50 feet twice a day for patients onset at least 6 months prior: with limited mobility, to 15 to 20 minutes of chair exercises at least twice a day for patients unable to walk or who are restricted to SECONDARY • Straining ≥25% of the time Inadequate diet bed rest. In addition, routine toileting in an upright position is Dehydration • Hard stools ≥25% of the time recommended 5 to 15 minutes after meals, as ignoring or suppressing Inadequate physical activity • Sensation of incomplete evacuation ≥25% of the time the urge to defecate can contribute to constipation.21 • Sensation of anorectal obstruction/blockage ≥25% of the time Use of certain medications: • Manual maneuvers to facilitate bowel movements ≥25% of the time • Aluminum-containing antacids • Antispasmodics • <3 bowel movements per week • Antidepressants

• Diuretics 12 • Anticonvulsants Table 3. Differentiation between normal stool evacuation and constipation • Pain medications VARIABLE NORMAL CONSTIPATION LIKELY (especially narcotics) • Calcium-channel blockers Frequency of stools ≥3 evacuations per week and ≥3 evacuations per week ≥3 evacuations per week • Nonsteroidal Weight of stools 35-150 g/day <35 g/day anti-inflammatory drugs Older age Pregnancy Weight of water in stools ca 70% <70% Mechanical obstructions: Time taken by gastrointestinal passage 2-5 days > 5 d • Colon cancer • Postsurgical abnormalities Endocrine/metabolic disorders: Pathophysiology of Opioid-Induced Constipation If symptoms of constipation persist despite instituting appropriate • Diabetes Opioids exert their effects through the activation of opioid receptors.17 lifestyle modifications, nonpharmacologic options can be combined • Hypothyroidism Opioid receptors exist throughout the central and the peripheral with and other drugs to treat OIC (Table 4).19 The most • Hypercalcemia nervous system, as well as the intestinal musculature and other common regimen for OIC involves combining a stimulant and a • Hyperparathyroidism tissues.8 Activating opioid receptors in the central nervous system stool softener to both increase muscle activity and lubricate and soften • Hypokalemia results in analgesia, whereas activation of opioid receptors in the gut stools, improving the ease with which stools pass.20 Laxatives do not • Uremia wall results in reduced gut motility, delayed gastric emptying, address the causes of OIC however, leading to inadequate symptom Neurologic conditions: increased sphincter tone, and a slower gut transit time.18 relief for many patients.18 Bulk-forming laxatives are often used as • Cerebrovascular events It appears as if endogenous opioids in the gastrointestinal tract first-line agents due to their low toxicity and cost, but in certain • Multiple sclerosis coordinate the contractile process under normal healthy conditions, patients, they can lead to abdominal distention and flatulence. • Parkinson’s disease suppressing motility when required, as it may be during situations Emollients such as sodium increase the moisture content of Psychological conditions: involving inflammation, stress, or trauma. fecal mass and are primarily used to prevent constipation in specific • Depression situations, such as during post-operative recovery, when straining • Anxiety

4 due to a bowel movement may be harmful to the patient. Osmotic Peripherally Acting μ-Opioid Receptor Antagonists laxatives promote water retention within the colon, leading to Another strategy to address OIC is to employ an increased pressure, which induces intestinal motility.21 to bind to opioid receptors without activating them, effectively blocking the receptors. While opioid antagonists such as 19 Table 4. Common laxatives act on both peripheral and central μ-opioid receptors, LAXATIVE MECHANISM OF ACTION belongs to a new class of drugs that selectively Stool softeners and emollients Lubricates and softens stools antagonizes peripheral μ-opioid receptors in the gastrointestinal 26-30 (eg, dioctyl sodium, docusate system, helping to relieve OIC while maintaining analgesic effects. sodium) As a charged derivative, methylnaltrexone has no effect on the central nervous system when given to humans.31 Stimulants and irritants (eg, Alters intestinal mucosal senna, ) permeability; stimulates muscle A 2-week, double-blind, randomized, placebo-controlled clinical trial activity and fluid secretions with a 3-month open-label extension was conducted to determine the efficacy and safety of the peripherally acting μ-opioid receptor Osmotic agents (eg, , Osmotic effect of salts leads to antagonist (PAMORA) methylnaltrexone in patients with OIC who magnesium salts, ) greater fluid retention in bowel were receiving opioid therapy for advanced illness. Significantly more lumen and a net increase of fluid patients treated with subcutaneous methylnaltrexone than placebo secretions in the small intestine experienced rescue-free laxation (defecation) within 4 hours after receiving the first dose of study drug (48% vs 15%, respectively; Bulk agents (eg, Increases fecal bulk and fluid P<0.001) (Figure 2).30 Pain scores remained similar between the two seed, bran) retained in the bowel lumen study groups at baseline and at each evaluation. Adverse events that occurred more frequently in the active treatment arm included Non-absorbable solutions (eg, Volume lavage abdominal pain, flatulence, nausea, increased body temperature, [PEG]) and dizziness.30

Enema Reflex evacuation Figure 2. Primary efficacy outcomes with methylnaltrexone.30

Aside from laxatives, OIC can also be treated using the chloride channel PRIMARY OUTCOMES activator , which stimulates bowel secretory action by 100 Placebo (N=71) Methylnaltrexone (N=62) increasing chloride and fluid secretion into the intestines. Clinical trials 90 have shown that lubiprostone improved the number of spontaneous 80 bowel movements, stool consistency, bloating, and global assessment 70 of constipation compared with placebo (P<0.05). Its most common 60 adverse event was nausea, occurring in 30.9% of patients. This side 48 52 effect, however, was found to be dose dependent, and it decreased 50 when administered with food.22 Figure 1 offers one suggested 40 algorithm to guide the order of possible pharmacotherapy for OIC. 30 Figure 1. Treatment algorithm for OIC. 20 15 8 10 0 Stool softeners and Laxaon within 4 Hr a er Laxaon within 4 Hr a er mild stimulation agents ≥2 of the First 4 Doses ≥ of the First 4 Doses (eg, senna) Investigational Peripherally Acting μ-Opioid Receptor Antagonists Methylnaltrexone and are the only PAMORA approved by the U.S. Food and Drug Administration for the treatment of OIC. Investigational compounds in this class that are currently tested Osmotic agents includes , and (TD-1211). An older PAMORA, , is also approved by the U.S. Food and Drug Administration, but only to accelerate the time to upper and lower gastrointestinal recovery following surgeries including partial bowel resection with primary anastomosis, and not for OIC.32 Issues Chloride channel activator Peripherally acting u-opioid receptor with alvimopan’s cardiovascular safety profile due to 7 myocardial antagonist infarctions versus 0 with placebo precluded its approval for OIC, but a recent Anesthetic and Analgesic Drug Products Advisory Committee meeting of the U.S. Food and Drug Administration held in June deemed The motility stimulant was originally approved to treat that this was not a class effect, and that the cardiovascular safety of irritable bowel syndrome with constipation and chronic idiopathic other PAMORAs could be assessed during postmarketing observational constipation (although not specifically opioid-induced constipation), studies rather than in prospective safety trials prior to approval.33-35 but was later removed from the market in 2007 due to concerns about Of the investigational PAMORAs, naloxegol is the furthest along in possible adverse cardiovascular effects.23 It is still available for use its clinical development program. It is a PEGylated conjugate of where allowed by the U.S. Food and Drug Administration in emergency that was designed using small-molecule polymer conjugate situations that are immediately life-threatening or serious enough technology. The PEGylation serves to alter its metabolism so that the to qualify for hospitalization.24 Its desired therapeutic effects are first-pass effect is reduced and its is increased and to achieved through activation of the 5-HT4 receptors of the enteric modify its distribution, reducing penetration into the central nervous nervous system in the gastrointestinal tract.25 system.23

5 In two identical phase 3, double-blind clinical trials (KODIAC-04 The most common adverse events reported with greater frequency and KODIAC-05), oral naloxegol 25 mg given once daily produced in the naloxegol arm compared with placebo were abdominal pain significantly higher response rates (defined as ≥3 spontaneous bowel (17.8% vs 3.3%), diarrhea (12.9% vs 5.9%), nausea (9.4% vs 4.1%), movements per week and an increase from baseline of ≥1 spontaneous headache (9.0% vs 4.8%), and flatulence (6.9% vs 1.1%). bowel movements for ≥9 of 12 weeks and for ≥3 of the final 4 weeks) than placebo did (study 04, 44.4% vs 29.4%, P=0.001; study 05, 39.7% Most of the naloxegol-emergent gastrointestinal adverse events vs 29.3%, P=0.02). Responses were also higher with naloxegol in a occurred early and were transient. Fourteen patients discontinued subpopulation of patients with an inadequate response to laxatives. naloxegol therapy due to abdominal pain. Two patients in each group Time to first postdose spontaneous bowel movement was shorter experienced major cardiovascular events, which were 37 and mean number of days per week with one or more spontaneous independently and prospectively adjudicated. bowel movements was higher with 25 mg of naloxegol compared with Phase 3 trials (ASCENT) in OIC in patients with chronic noncancer placebo in both studies (P<0.001). The pain scores and the daily opioid pain for another small-molecule PAMORA, bevenopran, were begun dose were similar among groups. Adverse events, which were in July 2013 but were then terminated by the manufacturer at the primarily gastrointestinal, occurred most frequently in the groups end of 2013 in light of the planned FDA Advisory Committee meeting treated with naloxegol 25 mg.36 regarding cardiovascular safety of PAMORAs, as well as due to In a long-term, open-label, randomized, parallel-group, enrollment challenges faced with the way the trials were designed. phase 3 safety and tolerability trial (KODIAC-08), outpatients It is uncertain yet whether the trials will be reinstated now that the with OIC who were taking 30 to 1000 -equivalent units results of the advisory meeting are available.38 Two completed phase per day for at least 4 weeks to treat noncancer pain were either 2 trials showed that bevenopran demonstrated statistically significant enrolled as new patients or from one of the prior naloxegol trials and and clinically relevant efficacy in patients suffering from OIC, and the randomized to naloxegol 25 mg once daily or usual-care treatment study drug was also well tolerated, with no evidence of drug-related for OIC as chosen by the investigator. Of the 804 patients enrolled, central or reversal of analgesia.39 the mean duration of exposure to naloxegol was 268.1 days and to usual care was 296.7 days.37

CASE STUDY 1 This 82-year-old woman presents with osteoporosis, atrial fibrillation, and congestive heart failure with multiple thoracic and lumbar compression fractures. Her pain is being treated with morphine extended-release 30 mg twice daily. She lives in an assisted living facility and ambulates with assistance and using a walker. She currently has fewer than 2 bowel movements per week with bloating. She uses bulk fiber agents without relief from her constipation symptoms: milk of magnesia, lactulose, and other osmotic agents resulted in abdominal pain.

What type of constipation is occurring? a) Primary b) Secondary c) Both This patient has both primary and secondary constipation. Assessment: What non-pharmacologic methods would you consider? a) Toileting b) Ambulation c) Fluid intake d) Fiber intake e) All of the above She could possibly be aided by all of the above non-pharmacologic methods such as toileting, ambulation, fluid intake, and fiber intake. Based on the AHRQ guidelines, what would be the next modality to be used? a) Senna b) Docusate sodium c) PEG d) Lubiprostone

Although some clinicians may think the patient should be treated with senna or docusate sodium next, the better choice would be lubiprostone, because she has already tried the other options, which did not bring her relief and actually caused her abdominal pain.

6 With two phase 2 trials completed, there are 3 phase 3 trials currently Three large, 12-week, randomized, double-blind, phase 3 clinical ongoing with the PAMORA known as naldemedine to determine its trials in patients with moderate to severe, chronic, nonmalignant pain long-term safety effects and its efficacy and safety in patients with were conducted, along with a prospectively planned pooled analysis of 40-44 OIC who are not receiving laxatives. Likewise, phase 2 trials of the two of these trial, which demonstrated that /naloxone PR PAMORA axelopran (TD-1211) have been completed, although a phase relieved pain more effectively than placebo and no less effectively than 3 program has not yet begun.45-48 oxycodone PR after 12 weeks. The combination was generally well tolerated. The most commonly reported adverse events were of Fixed Combination Oxycodone/Naloxone Prolonged-Release gastrointestinal origin, but numerically lower rates of constipation While much of the research being conducted for OIC treatments has were observed in the oxycodone/naloxone PR group compared with been for novel PAMORAs, there are other mechanisms also being the oxycodone PR group, offering some promise for those suffering studied. One such agent is a fixed combination of prolonged-release from OIC.49 oxycodone and prolonged-release naloxone (an opioid antagonist) in a single tablet with a 2:1 ratio.49

CASE STUDY 2 This 79-year-old man has a history of diabetic neuropathy, prostate cancer, simple prostatectomy, radiation, and lumbar and cervical degenerative disc disease. He is treated with gabapentin, , and transdermal 75 μg every 72 hours. His stools are very hard and cause straining. He has a daily painful bowel movement, which has worsened with increases in fentanyl dosing. Each day, he consumes 50 g of fiber, uses the treadmill, and drinks 3 L of fluids.

What type of constipation is occurring? a) Primary b) Secondary c) Both

This patient has secondary constipation that is purely opioid-induced. He is doing everything he should be doing as per the AHRQ guidelines – taking fiber, exercising, drinking plenty of fluids – and still he has constipation that was not present prior to receiving pain . His symptoms worsened as the opioid dose increased, also pointing toward a secondary cause. What pharmacologic therapy would you consider first? a) Lactulose b) Methylnaltrexone c) Docusate sodium d) Osmotic agents (lactulose)

Because the patient has daily bowel movements that are hard and accompanied by straining, stool softeners would be the first choice, so docusate sodium would be appropriate.The docusate helps a little with consistency, but he still has feelings of fullness and retention after evacuation. Appropriate choices at this point include the following except: a) Senna b) Lubiprostone c) Methylnaltrexone d) Psyllium

The patient has already optimized his non-pharmacologic routine with healthy behaviors. He has decreased bowel motility. All of the agents listed here will increase motility except for psyllium, which is the correct answer.

7 REFERENCES 1. Institute of Medicine (IOM). Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: The National Academies Press. 2011. 2. Manchikanti L, Abdi S, Atluri S, et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: part I – evidence assessment. Pain Physician. 2012;15:S1-S66. 3. Kalso E, Edwards JE, Moore RA, McQuay HJ. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain. 2004;112:372-380. 4. Benyamin R, Trescot AM, Datta S, et al. Opioid complications and side effects. Pain Physician. 2008;11(2 suppl):S105-S120. 5. Swegle JM, Logemann C. Management of common opioid-induced adverse effects. Am Fam Physician. 2006;74:1347-1354. 6. 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