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Sponsored by Global Education Group. Med Learning Group is the education partner.

This activity is supported by an educational grant from AstraZeneca.

JOURNAL SUPPLEMENTA CME/CE Supplement to PWJ—PAINWeek Journal

RELEASE DATE: December 1, 2014 EXPIRATION DATE: December 31, 2015

Program OverviewThis case-based enduring activity will cover the personalized care of patients with chronic pain.

Target Audience 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 analgesics used in the treatment of chronic pain, and their

safety, efficacy and indications- Recognize the most common opioid-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

FacultySanford M. Silverman, MDMedical DirectorComprehensive Pain MedicinePompano Beach, Florida

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.

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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 RelationshipAshley Marostica, RN, MSN Nothing to discloseAmanda Glazar, PhD Nothing to discloseMatthew Frese Nothing to discloseAndrea Funk Nothing to discloseChristina Gallo Nothing to discloseMelissa Johnson Nothing to discloseCheryl 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, medications, 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.

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The PAINWeekEnd™ Educational Summit Series brings live education about pain management to healthcare professionals through regional professional conferences. Each conference also includes an accredited continuing medical education activity hosted by a faculty chairperson. This supplement is designed to capture and expand upon some of the content of the PAINWeekEnd™ live program in print form. The management of chronic pain with opioids and the ensuing side effects will be discussed, with a particular focus on opioid-induced constipation (OIC), and how to communicate with patients about constipation.

CHRONIC PAIN OVERVIEWThe Institute of Medicine has estimated that more than 100 million Americans are living with pain that lasts from weeks to years, and that the financial costs of chronic pain total up to $635 billion annually.1 The high prevalence of chronic pain goes hand in hand with high rates of opioid therapy. Sales of opioid analgesics quadrupled between 1999 and 2010, with more than 256 million opioid prescriptions filled in 2009 alone.2 Opioid therapy is not without its side effects, though, and clinicians must be aware of the common side effects and ready to address them in a timely manner to prevent its toxicity from outweighing its effectiveness in treating pain. Of the side effects commonly associated with opioid use, constipation is the most prevalent.3 Opioid-induced constipation (OIC) is an expected part of opioid treatment that is unlikely to improve over time, and so it should be closely monitored and treated prophylactically, with a bowel regimen initiated as soon as it is deemed necessary.2,4,5

The American Society of Anesthesiologists Task Force on Chronic Pain Management and the American Society of Regional Anesthesia and Pain Medicine joined forces to created practice guidelines for the management of chronic pain. These guidelines recognize that many dif-ferent classes of pharmacologic agents can be used to treat chronic pain, including anticonvulsants, antidepressants, benzodiazepines, N-methyl-D-aspartate (NMDA) receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, skeletal muscle relaxants, and topical agents such as lidocaine, capsaicin, and ketamine.6 This range of medicines gives an idea of the heterogeneous nature of pain, as well as its range of severity, duration, and causes.

OPIOID-INDUCED SIDE EFFECTSOpioid therapy can be an effective tool, especially initially, in the quest to relieve patients’ chronic pain.7 It can be associated with a number of complications, however, that may limit its effectiveness, leading to early discontinuation, under-dosing, and inadequate analgesia. Some of the most common side effects found to be associated with opioid use include constipation, nausea, vomiting, respiratory depression, physical dependence, and sedation.4 Other issues that can arise with opioid therapy include pruritus, dizziness, tolerance, diversion, and hyperalgesia.4,5

Nausea occurs in approximately 25% of patients treated with opioids, and is usually transient, although treatment should be instituted if substantial nausea and vomiting occur. The central nervous system effects of opioid therapy, such as sedation and decreased cognition, are also usually transient, but treatment might be required to help cope with the undesirable effects. These adverse events seem to present at opioid initiation or with dose increases. Pruritus with opioid use occurs in 2% to 10% of patients, but the likelihood increases if the opioid is administered by epidural or intraspinal injections.5 Tolerance, which is a loss of analgesic potency, leads to requirements for dose increases with accompanying decreases in effectiveness over time. There is no cross tolerance with opioids, so the development of tolerance to one opioid does not necessarily confer tolerance to a different opioid. Therefore, switching opioids in a patient who has developed tolerance may require lowering the dose of the second opioid.4 Opioids have demonstrated effects on a number of hormones including testosterone, estrogen, luteinizing hormone, gonadotrophin releasing hormone, dehydroepiandrosterone, dehydroepiandrosterone sulfates, adrenocorticotropin, corticotropin-releasing hormone, and cortisol.

Hypogonadism and likely hypogonadotropic hypogonadism have correlated with side effects in men such as sexual dysfunction, depression, and decreased energy levels. Chronic opioid administration can lead to decreases in testosterone in a dose-dependent manner. Women can also have hormonal side effects of opioids, such as depression, dysmenorrhea, sexual dysfunction, and reduced bone mineral density.4

Hyperalgesia or hyperalgia is an increased sensitivity to pain that presents as increased pain despite increasing doses of opioids. Long-term opioid use or use of high doses may be associated with the development of hyperalgesia, which may be related to opioid metabolites and opioid-induced cell apoptosis.4

OPIOID-INDUCED CONSTIPATIONConstipation is an extremely common side effect of opioid treatment, occurring in 40% to 95% of patients, with the possibility of occurring after just a single dose.5 And, with the increase in the use of opioids, the absolute numbers of patients affected by OIC is also growing.8 In patients who require chronic analgesia, constipation can be a debilitating side effect that negatively impacts quality of life.4,9 With up to 56% of patients discontinuing their opioid treatment due to lack of efficacy or side effects, addressing constipation is critical.3,10

While OIC can occur in any patient treated with opioids, there are certain risk factors that can increase a patient’s likelihood of developing OIC. These risk factors include advanced age, female, type of opioid therapy, relative immobility of the patient, dehydration, altered nutritional intake, anal fissures, and any kind of mechanical obstruction within the gastrointestinal tract.11,12 Also, based on the numerous causes of constipation, which can be either primary (idiopathic) or secondary, it is important to determine if opioids are actually the cause of the constipation so that the treatment plan is accurately informed (Table 1).13

Table 1. Examples of primary (idiopathic) and secondary causes of constipation symptoms.13

PRIMARY (Idiopathic) IBS-C Normal-transit constipation Slow-transit constipation Defecatory or rectal evacuation disorders: • Pelvic floor dyssynergia• Hirschsprung’s disease• Anismus• Paradoxical pelvic floor

contraction• Functional rectosigmoid

obstruction• Spastic pelvic floor syndrome• Descending perineum syndrome

SECONDARYInadequate dietDehydrationInadequate physical activity

Use of certain medications:• Aluminum-containing antacids• Antispasmodics• Antidepressants • Diuretics• Anticonvulsants• Pain medications (especially narcotics)• Calcium-channel blockers• Nonsteroidal

anti-inflammatory drugs Older age Pregnancy Mechanical obstructions:• Colon cancer• Postsurgical abnormalitiesEndocrine/metabolic disorders:• Diabetes• Hypothyroidism• Hypercalcemia• Hyperparathyroidism• Hypokalemia• UremiaNeurologic conditions:• Cerebrovascular events• Multiple sclerosis• Parkinson’s diseasePsychological conditions:• Depression• Anxiety

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SECONDARYInadequate dietDehydrationInadequate physical activity

Use of certain medications:• Aluminum-containing antacids• Antispasmodics• Antidepressants • Diuretics• Anticonvulsants• Pain medications (especially narcotics)• Calcium-channel blockers• Nonsteroidal

anti-inflammatory drugs Older age Pregnancy Mechanical obstructions:• Colon cancer• Postsurgical abnormalitiesEndocrine/metabolic disorders:• Diabetes• Hypothyroidism• Hypercalcemia• Hyperparathyroidism• Hypokalemia• UremiaNeurologic conditions:• Cerebrovascular events• Multiple sclerosis• Parkinson’s diseasePsychological conditions:• Depression• Anxiety

Clinician-Patient CommunicationEffective communication between the clinician and the patient about constipation has been linked to improved outcomes, increased patient satisfaction, and decreased utilization of care. This communication can be strengthened by asking open-ended questions, actively listening to the patient, and displaying empathy during the patient’s visit.14 Because the topic of OIC deals with bowel habits that could be potentially embarrassing for the patient to discuss, it is important to actively seek out the information from patients that might uncover symptoms that need to be addressed. Patients must feel that their clinician takes them seriously, or they may be reticent to admit to having symptoms.15 When initiating an opioid regimen, it is safe to assume that all patients treated with opioids will experience some degree of bowel dysfunction during their treatment until proven otherwise. In order to properly assess whether OIC is an issue, an accurate medical history including current bowel habits and any current measures that may be used to ensure regularity can help to establish a baseline. It would also be helpful to capture any history of bowel function variability that the patient experienced either as an adult or a child. One aspect to keep in mind when discussing OIC with patients is that clinicians and patients may have vastly disparate definitions in mind regarding what constitutes constipation. The number of stools passed is just one of a number of criteria of constipation, and it is not even a necessary one for diagnosis, so if the correct questions are not asked, patients who think they do not have constipation may actually have 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, such as number of stools, straining, sensations while defecating, and consistency of stools (Table 2), as can Table 3, which differentiates normal bowel characteristics from constipation symptoms.12,16

Table 2. Rome III diagnostic criteria for constipation16

At least 2 of the following experienced for the last 3 months with onset at least 6 months prior:• Straining ≥25% of the time

• Hard stools ≥25% of the time

• Sensation of incomplete evacuation ≥25% of the time

• Sensation of anorectal obstruction/blockage ≥25% of the time

• Manual maneuvers to facilitate bowel movements ≥25% of the time

• <3 bowel movements per week

Pathophysiology of Opioid-Induced ConstipationOpioids exert their effects through the activation of opioid receptors.17

Opioid receptors exist throughout the central and the peripheral nervous system, as well as the intestinal musculature and other tissues.8 Activating opioid receptors in the central nervous system results in analgesia, whereas activation of opioid receptors in the gut wall results in reduced gut motility, delayed gastric emptying, increased sphincter tone, and a slower gut transit time.18

It appears as if endogenous opioids in the gastrointestinal tract coordinate the contractile process under normal healthy conditions, suppressing motility when required, as it may be during situations involving inflammation, stress, or trauma.

Of the three receptor classes in the enteric nervous system – δ, κ, and μ – the μ-opioid receptor seems to be the principal mediator of the effects of opioid agonists on the gastrointestinal tract. The binding of opioid agonists to these receptors inhibits the release of excitatory and inhibitory neurotransmitters, interrupting the contractions required for intestinal motility and reducing mucosal secretions. Administering exogenous opioids can cause opioid bowel dysfunction by decreasing peristalsis, reducing secretions into the gut, and increasing reabsorp-tion of fluid from the gut, leading to the formation of dry, hard stools that can be difficult to pass.19

TREATING OPIOID-INDUCED CONSTIPATION Both nonpharmacologic and pharmacologic treatment options are available for OIC. Its nonpharmacologic treatment is based on lifestyle modification. Typically, these measures include increasing the consumption of dietary fiber and fluids and increasing physical activity, all of which should begin at the initiation of opioid therapy and continue for the duration of treatment.20 According to the Agency for Healthcare Research and Quality (AHRQ) of the U.S Department of Health & Human Services, these changes in lifestyle should be implemented as soon as an individual is identified to be at risk for constipation. Fluid intake should measure at least 1.5 liters (or 6 cups) each day. Fiber provides the bulk needed by the colon to eliminate body waste. As fiber passes through the colon, it acts as a sponge and absorbs water, resulting in bulkier and softer stools. Then, waste moves through the body more quickly, allowing for easier and more regular bowel movements. For individuals whose fluid intake measures at least 1500 mL per day, a dietary fiber (including both insoluble and soluble fiber) intake between 20 and 35 grams minimum per day is recommended. Activity recommendations should be tailored to each individual’s physical abilities and general level of health, and can vary from walking 15 to 20 minutes or more once or twice a day for fully mobile patients, to ambulating at least 50 feet twice a day for patients 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 bed rest. In addition, routine toileting in an upright position is recommended 5 to 15 minutes after meals, as ignoring or suppressing the urge to defecate can contribute to constipation.21

If symptoms of constipation persist despite instituting appropriate lifestyle modifications, nonpharmacologic options can be combined with laxatives and other drugs to treat OIC (Table 4).19 The most common laxative regimen for OIC involves combining a stimulant and a stool softener to both increase muscle activity and lubricate and soften stools, improving the ease with which stools pass.20 Laxatives do not address the causes of OIC however, leading to inadequate symptom relief for many patients.18 Bulk-forming laxatives are often used as first-line agents due to their low toxicity and cost, but in certainpatients, they can lead to abdominal distention and flatulence. Emollients such as docusate sodium increase the moisture content of fecal mass and are primarily used to prevent constipation in specific situations, such as during post-operative recovery, when straining

Table 3. Differentiation between normal stool evacuation and constipation12

VARIABLE NORMAL CONSTIPATION LIKELY

Frequency of stools ≥3 evacuations per week and ≥3 evacuations per week ≥3 evacuations per week

Weight of stools 35-150 g/day <35 g/day

Weight of water in stools ca 70% <70%

Time taken by gastrointestinal passage 2-5 days > 5 d

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due to a bowel movement may be harmful to the patient. Osmotic laxatives promote water retention within the colon, leading to increased pressure, which induces intestinal motility.21

Table 4. Common laxatives19

Aside from laxatives, OIC can also be treated using the chloride channel activator lubiprostone, which stimulates bowel secretory action by increasing chloride and fluid secretion into the intestines. Clinical trials have shown that lubiprostone improved the number of spontaneous bowel movements, stool consistency, bloating, and global assessment of constipation compared with placebo (P<0.05). Its most common adverse event was nausea, occurring in 30.9% of patients. This side effect, however, was found to be dose dependent, and it decreased when administered with food.22 Figure 1 offers one suggested algorithm to guide the order of possible pharmacotherapy for OIC.

Figure 1. Treatment algorithm for OIC.

The motility stimulant tegaserod was originally approved to treat irritable bowel syndrome with constipation and chronic idiopathic constipation (although not specifically opioid-induced constipation), but was later removed from the market in 2007 due to concerns about possible adverse cardiovascular effects.23 It is still available for use where allowed by the U.S. Food and Drug Administration in emergency situations that are immediately life-threatening or serious enough to qualify for hospitalization.24 Its desired therapeutic effects are achieved through activation of the 5-HT4 receptors of the enteric nervous system in the gastrointestinal tract.25

Peripherally Acting μ-Opioid Receptor AntagonistsAnother strategy to address OIC is to employ an opioid antagonist to bind to opioid receptors without activating them, effectively blocking the receptors. While opioid antagonists such as naloxone act on both peripheral and central μ-opioid receptors, methylnaltrexone belongs to a new class of drugs that selectively antagonizes peripheral μ-opioid receptors in the gastrointestinal system, helping to relieve OIC while maintaining analgesic effects.26-30

As a charged naltrexone derivative, methylnaltrexone has no effect on the central nervous system when given to humans.31

A 2-week, double-blind, randomized, placebo-controlled clinical trial with a 3-month open-label extension was conducted to determine the efficacy and safety of the peripherally acting μ-opioid receptor antagonist (PAMORA) methylnaltrexone in patients with OIC who were receiving opioid therapy for advanced illness. Significantly more patients treated with subcutaneous methylnaltrexone than placebo experienced rescue-free laxation (defecation) within 4 hours after receiving the first dose of study drug (48% vs 15%, respectively; P<0.001) (Figure 2).30 Pain scores remained similar between the two study groups at baseline and at each evaluation. Adverse events that occurred more frequently in the active treatment arm included abdominal pain, flatulence, nausea, increased body temperature, and dizziness.30

Figure 2. Primary efficacy outcomes with methylnaltrexone.30

Investigational Peripherally Acting μ-Opioid Receptor AntagonistsMethylnaltrexone and naloxegol 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 includes bevenopran, naldemedine and axelopran (TD-1211).

An older PAMORA, alvimopan, 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 with alvimopan’s cardiovascular safety profile due to 7 myocardial 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 that this was not a class effect, and that the cardiovascular safety of other PAMORAs could be assessed during postmarketing observational studies rather than in prospective safety trials prior to approval.33-35

Of the investigational PAMORAs, naloxegol is the furthest along in its clinical development program. It is a PEGylated conjugate of naloxol that was designed using small-molecule polymer conjugate technology. The PEGylation serves to alter its metabolism so that the first-pass effect is reduced and its bioavailability is increased and to modify its distribution, reducing penetration into the central nervous system.23

LAXATIVE Stool softeners and emollients (eg, dioctyl sodium, docusate sodium)

Stimulants and irritants (eg, senna, bisacodyl)

Osmotic agents (eg, lactulose, magnesium salts, sorbitol)

Bulk agents (eg, psyllium seed, bran)

Non-absorbable solutions (eg, polyethylene glycol [PEG])

Enema

MECHANISM OF ACTION Lubricates and softens stools

Alters intestinal mucosal permeability; stimulates muscle activity and fluid secretions

Osmotic effect of salts leads to greater fluid retention in bowel lumen and a net increase of fluid secretions in the small intestine

Increases fecal bulk and fluid retained in the bowel lumen

Volume lavage

Reflex evacuation

Stool softeners and mild stimulation agents

(eg, senna)

Osmotic agents

Chloride channel activator Peripherally acting u-opioid receptor

antagonist

PRIMARY OUTCOMES

Placebo (N=71) Methylnaltrexone (N=62)100

90

80

70

60

50

40

30

20

10

0

15

48

8

52

Laxa�on within 4 Hr a�er ≥2 of the First 4 Doses

Laxa�on within 4 Hr a�er ≥ of the First 4 Doses

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In two identical phase 3, double-blind clinical trials (KODIAC-04 and KODIAC-05), oral naloxegol 25 mg given once daily produced significantly higher response rates (defined as ≥3 spontaneous bowel movements per week and an increase from baseline of ≥1 spontaneous 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% vs 29.3%, P=0.02). Responses were also higher with naloxegol in a subpopulation of patients with an inadequate response to laxatives. Time to first postdose spontaneous bowel movement was shorter and mean number of days per week with one or more spontaneous bowel movements was higher with 25 mg of naloxegol compared with placebo in both studies (P<0.001). The pain scores and the daily opioid dose were similar among groups. Adverse events, which were primarily gastrointestinal, occurred most frequently in the groups treated with naloxegol 25 mg.36

In a long-term, open-label, randomized, parallel-group, phase 3 safety and tolerability trial (KODIAC-08), outpatients with OIC who were taking 30 to 1000 morphine-equivalent units per day for at least 4 weeks to treat noncancer pain were either enrolled as new patients or from one of the prior naloxegol trials and randomized to naloxegol 25 mg once daily or usual-care treatment for OIC as chosen by the investigator. Of the 804 patients enrolled, the mean duration of exposure to naloxegol was 268.1 days and to usual care was 296.7 days.37

The most common adverse events reported with greater frequency in the naloxegol arm compared with placebo were abdominal pain (17.8% vs 3.3%), diarrhea (12.9% vs 5.9%), nausea (9.4% vs 4.1%), headache (9.0% vs 4.8%), and flatulence (6.9% vs 1.1%).

Most of the naloxegol-emergent gastrointestinal adverse events occurred early and were transient. Fourteen patients discontinued naloxegol therapy due to abdominal pain. Two patients in each group experienced major cardiovascular events, which were independently and prospectively adjudicated.37

Phase 3 trials (ASCENT) in OIC in patients with chronic noncancer pain for another small-molecule PAMORA, bevenopran, were begun in July 2013 but were then terminated by the manufacturer at the end of 2013 in light of the planned FDA Advisory Committee meeting regarding cardiovascular safety of PAMORAs, as well as due to enrollment challenges faced with the way the trials were designed. It is uncertain yet whether the trials will be reinstated now that the results of the advisory meeting are available.38 Two completed phase 2 trials showed that bevenopran demonstrated statistically significant and clinically relevant efficacy in patients suffering from OIC, and the study drug was also well tolerated, with no evidence of drug-related central opioid withdrawal or reversal of analgesia.39

C A S E S T U D Y 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) Primaryb) Secondaryc) Both

This patient has both primary and secondary constipation. Assessment: What non-pharmacologic methods would you consider?a) Toiletingb) Ambulationc) Fluid intaked) Fiber intakee) 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) Sennab) Docusate sodiumc) PEGd) 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.

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With two phase 2 trials completed, there are 3 phase 3 trials currently ongoing with the PAMORA known as naldemedine to determine its long-term safety effects and its efficacy and safety in patients with OIC who are not receiving laxatives.40-44 Likewise, phase 2 trials of the PAMORA axelopran (TD-1211) have been completed, although a phase 3 program has not yet begun.45-48

Fixed Combination Oxycodone/Naloxone Prolonged-ReleaseWhile much of the research being conducted for OIC treatments has been for novel PAMORAs, there are other mechanisms also being studied. One such agent is a fixed combination of prolonged-release oxycodone and prolonged-release naloxone (an opioid antagonist) in a single tablet with a 2:1 ratio.49

Three large, 12-week, randomized, double-blind, phase 3 clinical trials in patients with moderate to severe, chronic, nonmalignant pain were conducted, along with a prospectively planned pooled analysis of two of these trial, which demonstrated that oxycodone/naloxone PR relieved pain more effectively than placebo and no less effectively than oxycodone PR after 12 weeks. The combination was generally well tolerated. The most commonly reported adverse events were of gastrointestinal origin, but numerically lower rates of constipation were observed in the oxycodone/naloxone PR group compared with the oxycodone PR group, offering some promise for those suffering from OIC.49

C A S E S T U D Y 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, amitriptyline, and transdermal fentanyl 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) Primaryb) Secondaryc) 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 medication. His symptoms worsened as the opioid dose increased, also pointing toward a secondary cause. What pharmacologic therapy would you consider first?a) Lactuloseb) Methylnaltrexonec) Docusate sodiumd) 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) Sennab) Lubiprostonec) Methylnaltrexoned) 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.

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8. Aurilio C, Pace MC, Pota V, Sansone P. Chapter 6: Opioid induced constipation. In Catto-Smith AG, ed. Constipation – Causes, Diagnosis and Treatment. www.intechopen.com/books/constipation-causes-diagnosis-and-treatment/etiopathogenesis-incidence-and-diagnosis-of -opioid-induced constipation. Accessed July 21, 2014.

9. Camilleri M. Opioid-induced constipation: challenges and therapeutic opportunities. Am J Gastroenterol. 2011;106:835-842.

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11. Ahmedzai SH, Boland J. Constipation in people prescribed opioids. Clin Evid (online). 2010;2010. pii: 2407.

12. Clemens KE, Klaschik E. Managing opioid-induced constipation in advanced illness: focus on methylnaltrexone bromide. Ther Clin Risk Manag. 2010; 6:77-82.

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