s of
Exploring Relief and
A CME/CE Supplement to PWJ—PAINWeek Journal
RELEASE DATE: December 1, 2014
EXPIRATION DATE: December 31, 2015
Sponsored by Global Education Group. Med Learning Group is the education partner. This activity is supported by an educational grant from AstraZeneca.

Sanford M. Silverman, MD This case-based enduring activity will cover the personalized care of patients with 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 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 - 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.

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:
- Participate in the activity.
- Complete the post-test and activity evaluation through this link:
- 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 Nothing to disclose Nothing to disclose Nothing to disclose Nothing to disclose 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
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.
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
opioids, 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 constipation (OIC), and how to communicate with patients about
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 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 the financial costs of chronic pain total up to $635 billion annually.1 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 alone.2 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 gastrointestinal tract.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 ketamine.6 This range of medicines gives an idea of the heterogeneous nature of pain, as PRIMARY (Idiopathic) well as its range of severity, duration, and causes. Normal-transit constipation 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 • Antidepressants use include constipation, nausea, vomiting, respiratory depression, • Paradoxical pelvic floor physical dependence, and sedation.4 Other issues that can arise with • Anticonvulsants opioid therapy include pruritus, dizziness, tolerance, diversion, and • Functional rectosigmoid • Pain medications hyperalgesia.4,5 (especially narcotics) 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 the undesirable effects. These adverse events seem to present at opioid 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 by epidural or intraspinal injections.5 Tolerance, which is a loss of analgesic 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 different opioid. Therefore, switching opioids in a patient who has developed tolerance may require lowering the dose of the second • 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 sulfates, adrenocorticotropin, corticotropin-releasing hormone, and cortisol. 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-opioid receptor 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 symptoms that need to be addressed. Patients must feel that their that can be difficult to pass.19 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 dietary fiber 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, patients who think they do not have constipation may actually have absorbs water, resulting in bulkier and softer stools. Then, waste moves it by other parts of its definition. The components set forth by the through the body more quickly, allowing for easier and more regular 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 • Straining ≥25% of the time twice a day for patients unable to walk or who are restricted to bed rest. In addition, routine toileting in an upright position is • 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 • Anticonvulsants Table 3. Differentiation between normal stool evacuation and constipation12
• Pain medications 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 anti-inflammatory drugs Older age Pregnancy
Weight of water in stools Time taken by gastrointestinal passage Pathophysiology of Opioid-Induced Constipation
If symptoms of constipation persist despite instituting appropriate 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 laxatives and other drugs to treat OIC (Table 4).19 The most
• Hypercalcemia nervous system, as well as the intestinal musculature and other common laxative 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 results in analgesia, whereas activation of opioid receptors in the gut stools, improving the ease with which stools pass.20 Laxatives do not wall results in reduced gut motility, delayed gastric emptying, address the causes of OIC however, leading to inadequate symptom 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 docusate sodium increase the moisture content of involving inflammation, stress, or trauma.
fecal mass and are primarily used to prevent constipation in specific situations, such as during post-operative recovery, when straining 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 opioid antagonist increased pressure, which induces intestinal motility.21 to bind to opioid receptors without activating them, effectively blocking the receptors. While opioid antagonists such as naloxone Table 4. Common laxatives19
act on both peripheral and central μ-opioid receptors, methylnaltrexone belongs to a new class of drugs that selectively MECHANISM OF ACTION antagonizes peripheral μ-opioid receptors in the gastrointestinal Stool softeners and emollients Lubricates and softens stools system, helping to relieve OIC while maintaining analgesic effects.26-30 (eg, dioctyl sodium, docusate As a charged naltrexone derivative, methylnaltrexone has no effect on the central nervous system when given to humans.31 Stimulants and irritants (eg, Alters intestinal mucosal A 2-week, double-blind, randomized, placebo-controlled clinical trial senna, bisacodyl) permeability; stimulates muscle with a 3-month open-label extension was conducted to determine the activity and fluid secretions efficacy and safety of the peripherally acting μ-opioid receptor Osmotic agents (eg, lactulose, Osmotic effect of salts leads to antagonist (PAMORA) methylnaltrexone in patients with OIC who magnesium salts, sorbitol) 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, psyllium Increases fecal bulk and fluid P<0.001) (Figure 2).30 Pain scores remained similar between the two
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, abdominal pain, flatulence, nausea, increased body temperature, polyethylene glycol [PEG]) and dizziness.30 Reflex evacuation Figure 2. Primary efficacy outcomes with methylnaltrexone.30
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 Placebo (N=71) Methylnaltrexone (N=62)
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.
Stool softeners and Laxa‚on within 4 Hr a†er
Laxa‚on within 4 Hr a†er
mild stimulation agents ≥2 of the First 4 Doses
≥ of the First 4 Doses
Investigational Peripherally Acting μ-Opioid
In addition to methylnaltrexone, the only PAMORA currently approved by the U.S. Food and Drug Administration for the treatment of OIC, there are a number of investigational compounds in this class that are being tested, including naloxegol, 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 Chloride channel activator Peripherally acting u-opioid receptor 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 The motility stimulant tegaserod was originally approved to treat meeting of the U.S. Food and Drug Administration held in June deemed irritable bowel syndrome with constipation and chronic idiopathic that this was not a class effect, and that the cardiovascular safety of constipation (although not specifically opioid-induced constipation), other PAMORAs could be assessed during postmarketing observational but was later removed from the market in 2007 due to concerns about studies rather than in prospective safety trials prior to approval.33-35 possible adverse cardiovascular effects.23 It is still available for use Of the investigational PAMORAs, naloxegol is the furthest along in where allowed by the U.S. Food and Drug Administration in emergency its clinical development program. It is a PEGylated conjugate of situations that are immediately life-threatening or serious enough naloxol that was designed using small-molecule polymer conjugate to qualify for hospitalization.24 Its desired therapeutic effects are technology. The PEGylation serves to alter its metabolism so that the achieved through activation of the 5-HT4 receptors of the enteric first-pass effect is reduced and its bioavailability is increased and to nervous system in the gastrointestinal tract.25 modify its distribution, reducing penetration into the central nervous 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 and mean number of days per week with one or more spontaneous independently and prospectively adjudicated.37 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 morphine-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 opioid withdrawal 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 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) 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.

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 OIC who are not receiving laxatives.40-44 Likewise, phase 2 trials of the two of these trial, which demonstrated that oxycodone/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 oxycodone and prolonged-release naloxone (an opioid antagonist) in a single tablet with a 2:1 ratio.49 C A S E S T U DY 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) 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.

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. Practice guidelines for chronic pain management: an updated report by the American Society of Anesthesiologists Task Force on Chronic Pain Management and the American Society of Regional Anesthesia and Pain Medicine. Anesthesiology. 2010;112(4) 810-833.
7. Ballantyne JC, Shin NS. Efficacy of opioids for chronic pain: a review of the evidence. Clin J Pain. 2008;24:469-478.
8. Aurilio C, Pace MC, Pota V, Sansone P. Chapter 6: Opioid induced constipation. In Catto-Smith AG, ed. Constipation – Causes, Diagnosis -opioid-induced constipation. Accessed July 21, 2014. 9. Camilleri M. Opioid-induced constipation: challenges and therapeutic opportunities. Am J Gastroenterol. 2011;106:835-842.
10. Furlan AD, Sandoval JA, Mailis-Gagnon A, Tunks E. Opioids for chronic non-cancer pain: a meta-analysis of effectiveness and side effects. 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.
13. Johanson JF. Review of the treatment options for chronic constipation. MedGenMed. 2007;9(2):25. 14. Di Palma JA, Herrera JL. The role of effective clinician-patient communication in the management of irritable bowel syndrome and chronic constipation. J Clin Gastroenterol. 2012;46(9):748-751.
15. Davis MA. A perspective on cultivating clinical empathy. Complement Ther Clin Pract. 2009;15:76-79.
16. Rome III diagnostic criteria for functional gastrointestinal disorders. Accessed August 4, 2014. 17. Costantino CM, Gomes I, Stockton SD Jr, Lim MP, Devi LA. Opioid receptor heteromers in analgesia. Expert Rev Mol Med. 2012;14:e9.
18. Ahmedzai SH, Nauck F, Bar-Sela G, Bosse B, Leyendecker P, Hopp M. A randomized, double-blind, active-controlled, double-dummy, parallel-group study to determine the safety and efficacy of oxycodone/naloxone prolonged-release tablets in patients with moderate/severe, chronic cancer pain. Palliat Med. 2012;26(1):50-60.
19. Panchal SJ, Müller-Schwefe P, Wurzelmann JI. Opioid-induced bowel dysfunction: prevalence, pathophysiology and burden. Int J Clin Pract. 20. Kumar L, Barker C, Emmanuel A. Opioid-induced constipation: pathophysiology, clinical consequences, and management. Gastroenterol Res Pract. 2014;2014:141737.
21. McKay SL, Fravel M, Scanlon C. Management of constipation. Iowa City, IA: University of Iowa Gerontological Nursing Interventions Research Center, Research Translation and Dissemination Core; 2009 Oct. Guideline Summary NGC-7535.
22. Rivkin A, Chagan L. Lubiprostone: chloride channel activator for chronic constipation. Clin Ther. 2006;28(12):2008-2021.
23. Sprawls KS, Spierings EL, Tran D. Chapter 7: Drugs in development for opioid-induced constipation. In: Catto-Smith AG, ed. Constipation – cessed August 6, 2014.
24. U.S. Food and Drug Administration. Zelnorm (tegaserod maleate) information. informationforpatientsandproviders/ucm103223.htm. Accessed August 6, 2014. Last updated May 11, 2012.
25. Jing F, Zhang J. Metabolic kinetics of 5-hydroxytryptamine and the research targets of functional gastrointestinal disorders. Dig Dis Sci. 2014 Jun 12. [epub ahead of print] 26. De Schepper HU, Cremonini F, Park MI, Camilleri M. Opioids and the gut: pharmacology and current clinical experience. Neurogastroenterol 27. Kurz A, Sessler DI. Opioid-induced bowel dysfunction: pathophysiology and potential new therapies. Drugs. 2003;63:649-671.
28. Latasch L, Zimmerman M, Eberhardt B, Jurna I. Treatment of morphine-induced constipation with oral naloxone. [German] 29. Holzer P. Opioid antagonists for prevention and treatment of opioid-induced gastrointestinal effects. Curr Opin Anaesthesiol. 2010;23:616-622.
30. Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med. 31. Yuan CS. Clinical status of methylnaltrexone, a new agent to prevent and manage opioid-induced side effects. J Support Oncol. 2004;2:111-117.
32. Entereg ® (alvimopan) [package insert]. Lexington, MA: Cubist Pharmaceuticals, Inc.; 2013.
33. Mortenson E. Entereg® (alvimopan) OBD study GSK014 safety findings. 04-Adolor-Mortensen.pdf. Accessed August 6, 2014.
34. Food and Drug Administration Center for Drug Evaluation and Research. Briefing Document. Anesthetic and Analgesic Drug Products Advisory Committee Meeting. June 11-12, 2014. AndAnalgesicDrugProductsAdvisoryCommittee/UCM400205.pdf. Accessed August 6, 2014. 35. Bell K. FDA advisory committee advises against requiring CV outcomes trials for opioid-induced constipation drugs. June 12, 2014. Accessed August 6, 2014.
36. Chey WD, Webster L, Sostek M, Lappalainen J, Barker PN, Tack J. Naloxegol for opioid-induced constipation in patients with noncancer pain. N Engl J Med. 2014;370(25):2387-2396.
37. Webster L, Chey W, Tack J, Lappalainen J, Barker P, Sostek M. Long-term safety and tolerability of naloxegol in patients with opioid-induced constipation. Am J Gastroenterol. 2013;108(suppl 1):S568. Abstract 1880. 38. Form 10-K for Cubist Pharmaceuticals Inc. Annual Report. February 25, 2014. Accessed August 6, 2014. 39. Techner L, Singla N, Gabriel K, Mangano R. ADL5945, a potent orally bioavailable peripheral opioid receptor antagonist, improves bowel motility w/a low incidence/severity of GI AEs in a dose-dependent manner: results of 2 Ph 2 trials in opioid-induced constipation pts (45CL242 and 45CL243). J Pain. 2012;13(4 suppl):S84. Abstract 434.
40. A randomized, double-blind, placebo-controlled, single-ascending dose study to evaluate the safety and efficacy of S-297995 for the treatment of opioid-induced bowel dysfunction in subjects with chronic pain. NCT01122030.
41. A randomized, double-blind, placebo-controlled, parallel-group study of S-297995 for the treatment of opioid-induced constipation in subjects with non-malignant chronic pain receiving opioid therapy. NCT01443403. 42. A randomized double-blind, placebo-controlled, parallel-group, multicenter, phase 3 study to evaluate the long-term safety of naldemedine for the treatment of opioid-induced constipation in subjects with non-malignant chronic pain receiving opioid therapy. 43. A randomized, double-blind, placebo-controlled, parallel-group study of naldemedine in the treatment of opioid-induced constipation in subjects with non-malignant chronic pain receiving opioid therapy. NCT01965158. 44. A randomized, double-blind, placebo-controlled, parallel-group study of naldemedine in the treatment of opioid-induced constipation in subjects with non-malignant chronic pain receiving opioid therapy. NCT01993940.
45. A single-blind, pilot study to determine the tolerability and safety of TD-1211 in subjects with opioid-induced 46. A phase 1/phase 2, randomized, double-blind, multiple ascending dose study to assess the safety, pharmacokinetics, and effect on opioid analgesia of TD-1211 administered orally to healthy volunteers and to assess the safety, pharmacokinetics, and effect on bowel movements in subjects with opioid-induced constipation. NCT01040637.
47. A phase 2, randomized, double-blind, placebo-controlled, dose-escalation study to assess the safety, tolerability, and clinical activity of TD-1211 in subjects with opioid-induced constipation. NCT01333540.
48. A double-blind, randomized, placebo-controlled, parallel-group study to assess the safety and efficacy of TD-1211 in subjects with opioid-induced constipation. NCT01459926.
49. Burness CB, Keating GM. Oxycodone/naloxone prolonged-release: a review of its use in the management of chronic pain while counteracting opioid-induced constipation. Drugs. 2014;74(3):353-375.
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Transactions of the Royal Society of Tropical Medicine and Hygiene (2005) 99S, S1—S8 Public-private partnerships: an overviewRoy Widdus Initiative on Public-Private Partnerships for Health (IPPPH), Global Forum for Health Research, Received 16June 2005; accepted 17 June 2005 The development and marketing of medicines needed specifically to


J Oral Maxillofac Surg66:223-230, 2008 Outcomes of Placing Dental Implants in Patients Taking Oral Bisphosphonates: A Review of 115 Cases Bao-Thy Grant, DDS,* Christopher Amenedo, DDS,† Katherine Freeman, DrPH,‡ and Richard A. Kraut, DDS§ Purpose: In recent years, numerous cases of bisphosphonate-associated osteonecrosis of the jaw havebeen reported involving both intravenous and oral therapy regimens. The majority of these cases haveinvolved intravenous bisphosphonates. Subsequently, drug manufacturers and the US Food and DrugAdministration issued warnings about possible bisphosphonate-associated osteonecrosis of the jaw. TheAmerican Dental Association and the American Association of Oral and Maxillofacial Surgeons assembledexpert panels to formulate treatment guidelines. Both panels differentiated between patients receivingbisphosphonates intravenously and those receiving the drugs orally. However, the recommendationswere based on limited data, especially with regard to patients taking oral bisphosphonates. We wantedto ascertain the extent to which bisphosphonate-associated necrosis of the jaw has occurred in our dentalimplant patients. We also wanted to determine whether there was any indication that the bisphospho-nate therapy affected the overall success of the implants as defined by Albrektsson and Zarb.Patients and Methods: We identified 1,319 female patients over the age of 40 who had received dentalimplants at Montefiore Medical Center between January 1998 and December 2006. A survey about bisphos-phonate therapy was mailed to all 1,319 patients. Responses were received from 458 patients of whom 115reported that they had taken oral bisphosphonates. None had received intravenous bisphosphonates. All 115patients were contacted and informed about the risk of bisphosphonate-associated osteonecrosis of the jaw.Seventy-two patients returned to the clinic for follow-up clinical and radiological evaluation.Results: A total of 468 implants were placed in the 115 patients who reported that they had receivedoral bisphosphonate therapy. There is no evidence of bisphosphonate-associated osteonecrosis of thejaw in any of the patients evaluated in the clinic and those contacted by phone or e-mail reported nosymptoms. Of the 468 implants, all but 2 integrated fully and meet criteria for establishing implantsuccess. Implant success rates were comparable for patients receiving oral bisphosphonate therapy andthose not receiving oral bisphosphonate therapy.Conclusions: Guidelines for treatment of dental patients receiving intravenous bisphosphonate treatmentsshould be different than for patients taking the oral formulations of these medications. In this study, oralbisphosphonate therapy did not appear to significantly affect implant success. Implant surgery on patientsreceiving bisphosphonate therapy did not result in bisphosphonate-associated osteonecrosis of the jaw.Nevertheless, sufficient evidence exists to suggest that all patients undergoing implant placement should bequestioned about bisphosphonate therapy including the drug taken, the dosage, and length of treatment priorto surgery. For patients having a history of oral bisphosphonate treatment exceeding 3 years and those havingconcomitant treatment with prednisone, additional testing and alternate treatment options should be con-sidered.© 2008 American Association of Oral and Maxillofacial SurgeonsJ Oral Maxillofac Surg 66:223-230, 2008