newsred Rock Casino, Resort, and Spa

Transcription

1 Red Rock Casino, Resort, and Spa Las Vegas, NV Saturday, Sept 12 newsred Rock Casino, Resort, and Spa Las Vegas, NV news 1 THISISSUE 2 What s on the Schedule Today at PAINWeek? 4 Satellite Events at PAINWeek Haven t Got Time for the Pain 4 Are You Ready for REMS? 6 Fibromyalgia Is Real, and it Is Treatable 10 Pain Management Net Guide 12 Oral Presentations 13 Sometimes Laughter Really is the Best Medicine 18 Convention Exhibitors 19 Beyond the Casinos CE/CMECREDIT All evaluations can now be completed online. Log on to the online Conference Evaluation System at or click on the Request CE Credit logo at the Cybercafé. You may complete your evaluations using your laptop anywhere in the conference area, including your room, or at an available computer in the Cybercafé. You may also complete evaluations after the conference until September 30, See page 9 for more information RECAP Court is Now in Session The two-part United States vs. Pain Management Clinician firstof-its-kind mock trial conducted yesterday at PAINWeek 2009 featured Jennifer Bolen, JD; Dave Dokken, JD; Wayne Gross, JD; and Joanne Mehmert, CPC. The first part of the session offered fascinating insights into the mindset of prosecutors in cases involving physicians, and also offered valuable advice for potential defendants. Gross discussed the government s perspective when it comes to prosecuting cases involving wrongdoing on the part of clinicians. He asserted that the law enforcement community does not understand the healthcare world, and it behooves clinicians to always remain cognizant of this fact. In fact, Gross said that providers should learn how the law enforcement community thinks. It can keep you out of trouble in the first place, and then, should you find yourself in trouble, can help you get out of it, he said. Prosecutors have a simplistic view of the world: if you are the target of an investigation, to them you re either a criminal, or you re not. Gross said that RECAP We are all here because we believe in the amelioration of suffering, said Michael E. Schatman, PhD, CPE, as he opened his session, Buprenorphine-assisted Opioid Detoxification Combined with Psychosocial Intervention: A Novel Approach to the Over-medicated Chronic Non-cancer Pain Patient. We made the choice to go into pain management. But then if we do it, we have to do it right. At a conference where the presenters have often focused on the under-treatment of pain, Schatman made it clear that he does not believe that long-term opioid therapy is right for most patients. Does chronic therapy relieve suffering? he asked. Is there any evidence base for it? I m certainly not saying there are no patients who benefit from chronic opioid therapy; but in the majority of the cases I m seeing, patients are not benefitting from it. Schatman introduced what he called Portenoy s Floodgate, referring to a statement by pain pioneer Russ Portenoy: There appears to be a select he thinks prosecutors divide the medical world into four groups: the perfect doctor, who knows all the rules and regulations and is in perfect compliance; the real world, in which physicians actually practice medicine differently depending on their specialty (a distinction Gross said is often poorly understood, at best, by prosecutors); bad medicine/ malpractice, where bad medicine occurs, mistakes are made, and occasional subpopulation of patients with chronic pain that can achieve sustained partial analgesia from opioid therapy without the occurrence of intolerable side effects or the development of aberrant drug behaviors. Though it wasn t his intention, says Schatman, Portenoy s words opened a floodgate of opioid prescribing from pain management specialists who began to think they had carte-blanche to prescribe opioids. What we have now, according to Schatman, is a large number of patients who are on long-term opioid therapy, and little to no research that tells us whether long-term therapy is effective in improving quality of life. His characterization of the current literature included the following troubling phrases: anecdotal evidence, no randomized controlled trials, lack of measurement of treatment failures, weak in methodology, short in duration, no studies of long-term efficacy. Schatman also mentioned that the incidence of opioidinduced hyperalgesia is becoming more strongly established in the research. And misconduct occurs that subjects physicians to legal and/or administrative action; and criminals, who commit malpractice and are not practicing like a physician at all. The line between what constitutes legal malpractice and not practicing medicine at all is fuzzy, said Gross. Gross said that prescription-related cases often come down to the testimony of medical experts. Prosecutors hate relying on experts, because compelling testimony from competing expert witnesses is often given equal weight by jurors, and makes it easier for the defense to establish reasonable doubt. When selecting experts to testify, prosecutors look not just for academics, but someone who is also a practitioner, so the defense can t convey the expert as one who is out of touch with the real world. Prosecutors want experts who can convey to the jury the danger of addiction both to patients and to society. Dokken provided similar details from the perspective of the defense. He (continued on page 7) What is Your Exit Strategy if Long-term Opioid Therapy Isn t Working? there are the typical side effects of itching, constipation, nausea and vomiting, and recent evidence linking chronic opioid therapy to sleep apnea. Perhaps more disturbing, Schatman pointed to the research on how opioids affect patients psychosocially; one study showed that 23% of opioid patients suffer from depression, and 21% suffer from anxiety, whereas only 13% were bothered by gastrointestinal problems. We re so worried about constipation, but isn t it interesting that depression has a higher prevalence? Depression and anxiety disorder are more commonly associated with opioid use than with abuse of street drugs, including heroin. Very few studies have focused on quality of life at all, and any randomized controlled trials out there have been for only brief durations, Schatman added. Studies show that opioids contribute to decreases in activity level and function, and poor return-towork rates and work retention. So, if long-term opioid therapy isn t working for your patients, what is your (continued on page 8) S A T U R D A Y

2 2 news SATURDAY September 12, 2009 What s on the Schedule Today at PAINWeek? Welcome to the final day of the conference. The schedule today features a unique and timely Pain and Chemical Dependency track; a Rheumatology track of sessions that examine key issues in osteoarthritis, fibromyalgia, inflammatory arthropathies, and other topics; several Master Class sessions; a Complementary and Alternative Medicine track with presentations that offer fresh perspectives on natural approaches to pain management; poster and oral presentations; and several other essential sessions. conference registration Howard Heit, MD, starts the day s sessions with Addiction: What Is It? the first of several presentations in the Pain and Chemical Dependency track. As the course description states, too many healthcare professionals are not educated about the disease of addiction, which leads to fearfulness and reticence on the part of providers and inadequate pain control and reduced quality of life in patients suffering with pain. This course will provide an overview of the basic science behind addiction, clarifying several often poorly defined and understood concepts, including addiction and pseudo-addiction, physical dependence, and tolerance. The session will also feature discussion on the causes and consequences of diverted and abused opioid medications. Following the conclusion of Addiction: What Is It? Heit will present The Art and Science of Urine Drug Testing, with an encore scheduled for later in the morning. This presentation will focus on the diagnostic utility of urine drug testing when used in a therapeutic model of patient-centered care in a variety of treatment settings. Attendees will learn about practical approaches for incorporating urine drug testing into the treatment of chronic pain patients, the ways in which properly applied testing can help patients adhere to agreed-upon treatment plans, the effects opioid metabolism can have on testing, and more. As part of the Pain and Chemical Dependency track, Heit and Douglas Gourlay, MD, MSc, will present Managing the Inherited Pain Patient at 11:30am, with part 2 scheduled for this afternoon. The morning session will feature discussion on the increasing incidence of physical dependence on opioid medications, the challenges faced by patients who do not have reliable access to medications used to treat their pain, and assessment and management approaches that can be used by clinicians who have inherited patients who may be physically dependent on opioid medications. The presenters will explain the importance of learning to assess and treat agonist debt in these patients, the ways in which physical dependence can complicate the assessment of opioid responsiveness in chronic pain patients, and a patient-centered approach to risk assessment, management and pharmacologic optimization. Part 2 in the afternoon will follow up the information presented in the morning session by reviewing key questions to ask when performing an initial evaluation of a chronic pain patient, how to assess the patient s risk for opioid addiction, why it is important to treat the dominant disorder first in patients with comorbid pain and chemical dependency, and the differences between motive and behavior and why the two must be handled separately in patients who are chemically dependent on their medications. In Universal Precautions in the Treatment of the Chronic Pain Patient, Gourlay will discuss the current climate of opiophobia and the importance of both prescribers and patients exercising caution and sound judgment when using opioid medications. Gourlay will review the concept of Universal Precautions in pain medicine, risk assessment and oversight of high- and low-risk patients, and the benefits in terms of risk reduction and improved outcomes that come from approaching and treating pain and addiction as part of a continuum of conditions.

3 Red Rock Casino, Resort, and Spa Las Vegas, NV news 3 One of the more unique sessions today is the Academic Debate featuring Charles Argoff, MD; B. Eliot Cole, MD; and James McKoy, MD. Scheduled for 9:00am today, Fibromyalgia: Neuropathic or Rheumatologic Pain will address aspects of fibromyalgia that are potentially due to central nervous system generation, the characteristics of fibromyalgia that are associated with rheumatologic syndromes, fibromyalgia treatment approaches that are commonly employed by neurologists and rheumatologists, characteristics that differentiate fibromyalgia from other central neuropathic pain syndromes, and the differences between analgesic and adjuvant therapies for fibromyalgia. Speaking of neuropathic pain, David Fishbain, MD, will do just that during Improved Diagnosis of Neuropathic Pain. He will discuss several recently developed pain rating scales that measure neuropathic pain, along with new insights into the characteristics of several chronic pain conditions that have not been traditionally associated with neuropathic pain that are changing perceptions regarding its prevalence. Today s Rheumatology track features four presentations by Ronald Rapoport, MD: Osteoarthritis, which will explore osteoarthritis as more than just a degenerative condition, describe the pathophysiology of this condition, and review the benefits of ambulation and assistive devices; Inflammatory Arthropathies, in which Dr. Rapoport will describe the common and uncommon inflammatory arthropathies, discuss diagnostic methods, and prepare practitioners to better care for those in pain; Fibromylagia, which will review new data that suggests there is loss of cortical grey matter and other changes associated with fibromyalgia, the defining clinical characteristics of this condition, and current treatment options; and Diagnosis and Treatment of Rheumatoid Arthritis, which will review the clinical presentation and symptoms associated of rheumatoid arthritis (RA), diagnostic tests used to assess patients for RA, and pharmacologic treatment options for patients with RA. There are two Master Class sessions scheduled for today. In the first, Quantitative Examination of Pain Patients, Charles Argoff, MD, CPE, will address quantitative sensory testing (both general methodology and specific tests) for the evaluation of neuropathic pain and the peripheral receptors tested by these techniques. Dr. Argoff will also discuss a comprehensive neuropathic pain evaluation protocol that is based upon these tests. The first session of this twopart presentation begins at 10:30am, with part 2 immediately following at 11:30am. The second Master Class session for today is Thoracic Outlet Syndrome, presented by Allen Togut, MD. This two-part presentation (part 1 begins at 10:30am; part 2 at 11:30am) will examine the clinical characteristics and pathogenesis of thoracic outlet syndrome, approaches for diagnosis and assessing patients for this syndrome, and options for nonsurgical management. Finally, set aside time to attend Practical Perspectives for the Frontline Clinician, the midday symposium presented by Gilbert Fanciullo, MD, MS, and Jane Ballantyne, MD. Fanciullo and Ballantyne will discuss barriers that lead to undertreatment of pain, including providers lack of knowledge and education regarding the effective use of opioid medications in the treatment of chronic noncancer pain. They will also review the clinical implications of the opioid therapy guidelines recently released by the American Pain Society and American Academy of Pain Medicine, current and emerging opioid analgesics and the need to effectively assess their risks and benefits in order to minimize abuse potential and optimize pain relief, strategies for effectively integrating risk management tools and assessment and monitoring strategies into clinical practice, and relevant legal and regulatory statutes surrounding the treatment of pain with opioids and the effect they can have on clinical practice. What is your instant device missing? Comprehensive test results only AIT can deliver. A negative result on your instant device isn t always proof of non-compliance. When prescribing pain medication, having reliable test results is the final piece of the puzzle. That s why our lab was one of the first in the country to customize a testing program for physicians to monitor patients on prescribed therapies. good science. good decisions. good practice. (800) goodscience@aitlabs.com

4 4 news SATURDAY September 12, 2009 RECAP Haven t Got Time for the Pain We know that for the vast majority of illnesses, disease contraction and progression is significantly more pronounced in aging populations. This is as true in oncology as it is in endocrinology as it is in cardiology. In those specialties, however, there is more literature around the underlying reasons that susceptibility to disease increases with age than there is in the field of pain management. In his Thursday afternoon presentation, Haven t Got Time for the Pain, B. Eliot Cole MD, MPA, CPE, walked through the best of the literature on the impact of aging on arthritis, back and neck pain, breakthrough pain, and other types of pain. His literature search spanned the globe, but the lack of thorough research into the relationship between of aging and pain has hindered a deeper understanding in the field, Cole says. In one anecdote, an elderly patient asks his doctor about pain developing in his left knee. Well, says the doctor, that s to be expected. You re getting older, and this is fairly common. Yes, says the patient, but my right knee is the same age, and it feels totally fine. Cole then turned his attention to what we do know about pain and aging, including the fact that 60% of cancers and 70% of cancer deaths are among the over- 65 age group. As the population ages the group of people over age 100 is the fastest growing segment of the population the incidence of all kinds of cancers increases dramatically, along with the pain associated with cancer and its treatment. At some point, all men will develop cancer, but the same is not true for women, Cole said. The aggressiveness of the disease, of course, is significantly different for an older patient. Thus, prostate cancer treatment for a man who is diagnosed in his 80s will have much gentler treatment than a man diagnosed in his late 40s or early 50s. Cole talked about the aging of the cervical spine, even in the absence of underlying medical conditions. In one RECAP Are You Ready for REMS? study that looked at patients in middle age 10 years after a baseline MRI was taken, the aging of the cervical spine was pronounced. Another 10 years from now, Cole said, we ll have significantly nastier MRIs than we do today. We see pathology, but not what is causing it. Lower back pain and neck pain are common among adults, and if you have one, according to Cole, you ll soon have the other. If you re in pain long enough, you ll also probably end up with depression. Patients with depression are more than twice as likely to have an episode of disabling back pain. If I wasn t a psychiatrist, which I happen to be, I need to be thinking about related conditions. We ve been accused of too liberally using antidepressants, but maybe we re not using them enough. Obesity, said Cole, is the second strongest risk factor for knee osteoarthritis. There is an interesting correlation in the research between thighe circumference and predictive lack of coronary artery disease. It may seem counterintuitive to encourage a patient with chronic pain to exercise, but Cole suggests doing just that, in some cases. He also talked about pain patients pacing themselves throughout the day, rather than trying to push themselves to finish the laundry, the dishes, and the cleaning all at one time. Strangely, Cole said, turns out there isn t a lot of research that supports pacing. There are lots of theories, but no good studies. Empirically, we all believe pacing works, but a couple hundred years ago, we thought bleeding was good too! Other interesting research cited by Cole includes the fact that those with few or no social ties are more likely to experience pain that will interfere with daily living. Lower socioeconomic status, too, contributes to higher incidences of pain suffering and worse outcomes, though the reasons for this remain elusive. We still need better definitions, better models, and research with multiple inputs to untangle the implications of socioeconomic differences. In a fast-moving Thursday afternoon session sponsored by Cephalon, Michael J. Brennan, MD; Steven D. Passik, PhD; and Jennifer Bolen, JD, presented Are You Ready for REMS? a high-level overview of the information physicians are going to need to know to prepare to comply with REMS once the final program is implemented. Passik talked about the necessity for REMS and noted that, we are where we re at today due to a complex mix of medical, social, and political factors. He said that the FDA is under tremendous pressure from Congress to stop the dying associated with opioid medication misuse and abuse. The agency wants to do the right thing, said Passik, but is getting input from many stakeholders, making it vital that physicians and other members of the pain management community make their voices heard and share their opinions and insight with the FDA. Jennifer Bolen, JD, briefly discussed several practical and legal implications of REMS. She said that even though REMS will be burdensome, the documentation and educational materials for patients that will be required will be helpful for physicians in terms of keeping complete medical records. Other REMS documentation may help facilitate compliance with DEA requirements. REMS medication agreements will be important in a legal sense in terms of certifying that providers understand the risks, have expressed them to patients, and have gotten informed consent. Several legal matters remain to be settled, she said. What does it mean when you sign a REMS document? What if you don t follow all requirements? Will in-house counsel let physicians and pharmacist sign the REMS agreements? Michael Brennan, MD, asked Why bother with REMS? Because, he said, non-compliance will not be an option, and reliance on products without REMS may lead to inadvertent undertreatment of pain in appropriate patients. REMS will ensure that the right medications continue to be prescribed for appropriate patients; facilitate the necessary dialogue with patients about abuse, misuse, and addiction; and improve communication with patients on taking and handling medication responsibly. To prepare, physicians are going to have to coordinate with their office or clinic to train staff and monitor procedures and documentation, educate patients about REMS and its implications, review current prescribing habits, and stay informed about the latest developments and requirements. Physicians can go to to view educational videos and sign up for updates. Satellite Events at PAINWeek 2009 PAINWeek 2009 will feature several industry-supported satellite events designed to complement the educational experience of PAINWeek attendees. You may attend these educational satellite sessions free of charge. SATURDAY, SEPTEMBER 12 Once-Daily Approach to the Treatment of Muscle Spasm (Course Code: PTH-02) Time: 12:00pm - 1:00pm Location: Pavilion Ballroom Brought to you by Cephalon, Inc. This non-cme, promotional program provides an overview of acute muscle spasm. The scheduled speaker for this event is Joseph Valenza, MD, who will address a range of topics, including guidelines for classification and diagnosis, the importance of breaking the spasm-pain-spasm cycle, and treatment options, including a review of skeletal muscle relaxants for painful musculoskeletal conditions. Case studies illustrating acute muscle spasm will be presented, followed by an interactive Q&A session. For more information, or to register for this event, visit Practical Perspectives for the Frontline Clinician (Course Code: SYM-01) Time: 12:45pm - 2:15pm Location: Charleston Ballroom Supported by an educational grant from PriCara, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc., administered by Ortho-McNeil Janssen Scientific Affairs, LLC. This educational activity is designed to provide clinicians with the framework for safer use of opioids and more efficacious care for patients with chronic noncancer pain and also for minimizing the risk associated with their use. The scheduled speakers for this event are Gilbert J. Fanciullo, MD, MS; Jane C. Ballantyne, MD; and Robert L. Barkin, PharmD, MBA, FCP. They will identify the barriers that interfere with appropriate opioid management in nonmalignant pain; explore the clinical implications of the 2009 AAPM/APS Consensus on opioid therapy and nonmalignant pain; review the terminology and legal/ regulatory statutes surrounding the treatment of pain with opioids; discuss ways in which practitioners can integrate risk management tools and assessment and monitoring strategies into clinical practice; and review the risks and benefits of current and emerging opioid analgesics to minimize abuse potential and optimize pain relief. For more information, or to register for this event, visit

5 DD PRINTED IN USA. 2009, Lilly USA, LLC. ALL RIGHTS RESERVED.

6 6 news SATURDAY September 12, 2009 PREVIEW Fibromyalgia Is Real, and it Is Treatable Fibromyalgia is defined by three months of pain in 11 of 18 tender points, says Ronald Rapoport, MD. A difficult illness to treat, those stricken with the disease can be an enormous challenge, as many of them carry a burden that is not obvious; in other words, there may be an underlying reason why they have this syndrome that will add to whatever other diagnoses they may have, he explains. For example, a history of sexual or physical abuse is common among those with fibromyalgia. Rapoport will address these challenges today, also covering the etiology of the condition, the ways in which patients present physically and in terms of history, criteria that are available to secure a diagnosis, and treatment. His discussion on treatment will focus on the three medications Lyrica (pregabalin), Cymbalta (duloxetine HCl), and Savella (milnacipran HCl) that are FDA-approved to treat fibromyalgia. They can work alone; all three are effective he notes. But it is not uncommon that we need combination therapy to achieve our goal. Although Rapoport plans to address some of the more recent research findings that are important, he feels it is more important to go over the ones that are here and ongoing. Even with three drugs approved by the FDA for the treatment of fibromyalgia, Rapoport acknowledges that many people think it doesn t exist. However, he explains, we have come to a fairly reasonable conclusion that fibromyalgia is a disease in which there is an abnormality of the central processing of the pain stimulus. Our bodies have an ascending pathway in which the impulse is sent to the brain and a descending pathway in which there is modulation of that pain impulse. In fibromyalgia, there may be an abnormality in one or both of these areas. The resistance by some to acknowledge fibromyalgia as a legitimate condition, Rapoport believes, is potentially due to the struggles in diagnosing and treating patients with the condition. Some may feel it s just easier not to recognize the illness. It s difficult to secure the diagnosis of any illness in which there is not a clear objective test to help us out, and there s no fibromyalgia titer, says Rapoport. There are American criteria that are a kind of screening test for many of us, but the question comes up, Can a patient have fibromyalgia and yet not strictly fulfill these criteria? And the answer is yes. What s more, These patients are not a joy to take care of a lot of the time; they can be demanding, even more so than other patients we have, Rapoport adds. Many physicians feel that it s a disease of depression and an inability of these patients being able to cope. But that has been proven not to be true. There is something different that these patients have, and there have been some objective findings; one of clearest is that in functional MRI data, people with fibromyalgia separate from others. Also, there have been different levels among patients with fibromyalgia when looking at other mediators of pain, such as substance P. But there s not a simple test. It s a challenge; it takes a whole lot of doctoring to take care of these patients. Rapoport hopes that attendees of his presentation will come away with an understanding that fibromyalgia is an entity that clearly exists. This is a treatable illness, but it takes time and patience. Monotherapy can work, although combination therapy usually has an edge, and this is an illness that is not one of exclusion. We can secure the diagnosis fairly well. PHYSICIANS AND OTHER HEALTHCARE PROVIDERS MUST BECOME FAMILIAR WITH THE IMPORTANT WARNINGS IN THIS LABEL. Reports of serious adverse events, including deaths in patients treated with FENTORA have been reported. Deaths occurred as a result of improper patient selection (e.g., use in opioid non-tolerant patients) and/or improper dosing. The substitution of FENTORA for any other fentanyl product may result in fatal overdose. FENTORA is indicated only for the management of breakthrough pain in patients with cancer who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking around-the-clock medicine consisting of at least 60 mg of oral morphine daily, at least 25 mcg of transdermal fentanyl/hour, at least 30 mg of oxycodone daily, at least 8 mg of oral hydromorphone daily, or an equianalgesic dose of another opioid daily for a week or longer. FENTORA is not indicated for use in opioid non-tolerant patients including those with only as needed (PRN) prior exposure. FENTORA is contraindicated in the management of acute or postoperative pain including headache/migraine. Life-threatening respiratory depression could occur at any dose in opioid non-tolerant patients. Deaths have occurred in opioid non-tolerant patients. When prescribing, do not convert patients on a mcg per mcg basis from Actiq to FENTORA. Carefully consult the Initial Dosing Recommendations table. (See DOSAGE AND ADMINISTRATION, Table 7.) When dispensing, do not substitute a FENTORA prescription for other fentanyl products. Substantial differences exist in the pharmacokinetic profile of FENTORA compared to other fentanyl products that result in clinically important differences in the extent of absorption of fentanyl. As a result of these differences, the substitution of FENTORA for any other fentanyl product may result in fatal overdose. Special care must be used when dosing FENTORA. If the breakthrough pain episode is not relieved after 30 minutes, patients may take ONLY one additional dose using the same strength and must wait at least 4 hours before taking another dose. (See DOSAGE AND ADMINISTRATION.) FENTORA contains fentanyl, an opioid agonist and a Schedule II controlled substance, with an abuse liability similar to other opioid analgesics. FENTORA can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing FENTORA in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion. Schedule II opioid substances which include morphine, oxycodone, hydromorphone, oxymorphone, and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression. Patients and their caregivers must be instructed that FENTORA contains a medicine in an amount which can be fatal to a child. Patients and their caregivers must be instructed to keep all tablets out of the reach of children. (See Information for Patients and Caregivers for disposal instructions.) FENTORA is intended to be used only in the care of opioid tolerant cancer patients and only by healthcare professionals who are knowledgeable of and skilled in the use of Schedule II opioids to treat cancer pain. The concomitant use of FENTORA with strong and moderate cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, and may cause potentially fatal respiratory depression Cephalon, Inc. All rights reserved. FEN-2009P-PM May 2009 Printed in USA. DON T MAKE THEM COUNT THE MOMENTS. Make their moments count with the early-onset relief of FENTORA. 1 Indicated only for the management of breakthrough pain in opioid tolerant patients with cancer. For more information about FENTORA, please visit or call Cephalon at Please see boxed warning and brief summary of prescribing information on adjacent pages. Reference: 1. Portenoy RK, Taylor D, Messina J, Tremmel L. A randomized, placebo-controlled study of fentanyl buccal tablet for breakthrough pain in opioid-treated patients with cancer. Clin J Pain. 2006;22(9):

7 Red Rock Casino, Resort, and Spa Las Vegas, NV news 7 Mock Trial (continued from page 1) said that prosecutions often begin as a bolt from the blue government agents show up at your practice with a search warrant looking for medical records and business records. What should providers do in this situation? First, said Dokken, physicians must remember that they have certain rights, the first and foremost of which is the right to remain silent. If their practice is raided, physicians should call their attorney for guidance. Dokken stressed to the audience that they did not have to answer investigators questions. Defer them to your attorney. This whole process is a bit of shock and awe investigators are hoping to invoke an irrational response and get statements to use against you in an investigation. If they don t arrest you they do not have to advise you of your Miranda rights. They will also talk to your staff, so you have to make them aware that they too do not have to talk, because now they are potential witnesses against you. Your colleagues in the office need to know the same things, said Dokken. It is not uncommon for prosecutors to attempt to charge them with the same offenses and work to turn them against you in hopes of lessening their charges. If you don t think that the offer to avoid loss of their license, ability to earn a living, and their reputation in exchange for testifying against you isn t powerfully persuasive, think again, said Dokken. FENTORA (fentanyl buccal tablet) CII BRIEF SUMMARY: Please see full prescribing information. PHYSICIANS AND OTHER HEALTHCARE PROVIDERS MUST BECOME FAMILIAR WITH THE IMPORTANT WARNINGS IN THIS LABEL. Reports of serious adverse events, including deaths in patients treated with FENTORA have been reported. Deaths occurred as a result of improper patient selection (e.g., use in opioid non-tolerant patients) and/or improper dosing. The substitution of FENTORA for any other fentanyl product may result in fatal overdose. FENTORA is indicated only for the management of breakthrough pain in patients with cancer who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking around-theclock medicine consisting of at least 60 mg of oral morphine daily, at least 25 mcg of transdermal fentanyl/hour, at least 30 mg of oxycodone daily, at least 8 mg of oral hydromorphone daily, or an equianalgesic dose of another opioid daily for a week or longer. FENTORA is not indicated for use in opioid non-tolerant patients including those with only as needed (PRN) prior exposure. FENTORA is contraindicated in the management of acute or postoperative pain including headache/ migraine. Life-threatening respiratory depression could occur at any dose in opioid non-tolerant patients. Deaths have occurred in opioid non-tolerant patients. When prescribing, do not convert patients on a mcg per mcg basis from Actiq to FENTORA. Carefully consult the Initial Dosing Recommendations table. (See DOSAGE AND ADMINISTRATION, Table 7.) When dispensing, do not substitute a FENTORA prescription for other fentanyl products. Substantial differences exist in the pharmacokinetic profile of FENTORA compared to other fentanyl products that result in clinically important differences in the extent of absorption of fentanyl. As a result of these differences, the substitution of FENTORA for any other fentanyl product may result in fatal overdose. Special care must be used when dosing FENTORA. If the breakthrough pain episode is not relieved after 30 minutes, patients may take ONLY one additional dose using the same strength and must wait at least 4 hours before taking another dose. (See DOSAGE AND ADMINISTRATION.) FENTORA contains fentanyl, an opioid agonist and a Schedule II controlled substance, with an abuse liability similar to other opioid analgesics. FENTORA can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing FENTORA in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion. Schedule II opioid substances which include morphine, oxycodone, hydromorphone, oxymorphone, and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression. Patients and their caregivers must be instructed that FENTORA contains a medicine in an amount which can be fatal to a child. Patients and their caregivers must be instructed to keep all tablets out of the reach of children. (See Information for Patients and Caregivers for disposal instructions.) FENTORA is intended to be used only in the care of opioid tolerant cancer patients and only by healthcare professionals who are knowledgeable of and skilled in the use of Schedule II opioids to treat cancer pain. The concomitant use of FENTORA with strong and moderate cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, and may cause potentially fatal respiratory depression. INDICATIONS AND USAGE (See BOXED WARNING and CONTRAINDICATIONS) FENTORA is indicated only for the management of breakthrough pain in patients with cancer who are already receiving and who are tolerant to around-the-clock opioid therapy for their underlying persistent cancer pain. Patients considered opioid tolerant are those who are taking around-the-clock medicine consisting of at least 60 mg of oral morphine daily, at least 25 mcg of transdermal fentanyl/hour, at least 30 mg of oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid daily for a week or longer. This product must not be used in opioid non-tolerant patients because life-threatening hypoventilation and death could occur at any dose in patients not on a chronic regimen of opioids. For this reason, FENTORA is contraindicated in the management of acute or postoperative pain. FENTORA is intended to be used only in the care of opioid tolerant cancer patients and only by healthcare professionals who are knowledgeable of and skilled in the use of Schedule II opioids to treat cancer pain. CONTRAINDICATIONS FENTORA is contraindicated in opioid non-tolerant patients. FENTORA is contraindicated in the management of acute or postoperative pain including headache/migraine. Life-threatening respiratory depression and death could occur at any dose in opioid non-tolerant patients. FENTORA is contraindicated in patients with known intolerance or hypersensitivity to any of its components or the drug fentanyl. WARNINGS (See BOXED WARNING) When prescribing, DO NOT convert a patient from Actiq to FENTORA, without following the instructions found in the prescribing information as Actiq and FENTORA are not equivalent on a microgram per microgram basis. FENTORA is NOT a generic version of Actiq. When dispensing, DO NOT substitute a FENTORA prescription for an Actiq prescription under any circumstances. FENTORA and Actiq are not equivalent. Substantial differences exist in the pharmacokinetic profile of FENTORA compared to other fentanyl products including Actiq that result in clinically important differences in the rate and extent of absorption of fentanyl. As a result of these differences, the substitution of the same dose of FENTORA for the same dose of Actiq or any other fentanyl product may result in a fatal overdose. There are no safe conversion directions available for patients on any other fentanyl products (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.) Therefore, for opioid tolerant patients, the initial dose of FENTORA should be 100 mcg. Each patient should be individually titrated to provide adequate analgesia while minimizing side effects. (See DOSAGE AND ADMINISTRATION.) Use with CNS Depressants The concomitant use of other CNS depressants, including other opioids, sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers, skeletal muscle relaxants, sedating antihistamines, potent inhibitors of cytochrome P450 3A4 isoform (e.g., erythromycin, ketoconazole, and certain protease inhibitors), and alcoholic beverages may produce increased depressant effects. Hypoventilation, hypotension, and profound sedation may occur. FENTORA is not recommended for use in patients who have received MAO inhibitors within 14 days, because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Pediatric Use: The safety and efficacy of FENTORA have not been established in pediatric patients below the age of 18 years. Patients and their caregivers must be instructed that FENTORA contains a medicine in an amount which can be fatal to a child. Patients and their caregivers must be instructed to keep tablets out of the reach of children. (See SAFETY AND HANDLING, PRECAUTIONS, and MEDICATION GUIDE for specific patient instructions.) Drug Abuse, Addiction and Diversion of Opioids: FENTORA contains fentanyl, a mu-opioid agonist and a Schedule II controlled substance with high potential for abuse similar to hydromorphone, methadone, morphine, oxycodone, and oxymorphone. Fentanyl can be abused and is subject to misuse, and criminal diversion. Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. However, all patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common. Drug-seeking behavior is very common in addicts and drug abusers. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Since FENTORA tablets may be diverted for non-medical use, careful record keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised. Proper assessment of patients, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. FENTORA should be handled appropriately to minimize the risk of diversion, including restriction of access and accounting procedures as appropriate to the clinical setting and as required by law. Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product. Physical Dependence and Withdrawal: The administration of FENTORA should be guided by the response of the patient. Physical dependence, per se, is not ordinarily a concern when one is treating a patient with cancer and chronic pain, and fear of tolerance and physical dependence should not deter using doses that adequately relieve the pain. Opioid analgesics may cause physical dependence. Physical dependence results in withdrawal symptoms in patients who abruptly discontinue the drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, nalmefene, or mixed agonist/antagonist analgesics (pentazocine, butorphanol, buprenorphine, nalbuphine). Physical dependence usually does not occur to a clinically significant degree until after several weeks of continued opioid usage. Tolerance, in which increasingly larger doses are required in order to produce the same degree of analgesia, is initially manifested by a shortened duration of analgesic effect, and subsequently, by decreases in the intensity of analgesia. Respiratory Depression: Respiratory depression is the chief hazard of opioid agonists, including fentanyl, the active ingredient in FENTORA. Respiratory depression is more likely to occur in patients with underlying respiratory disorders and elderly or debilitated patients, usually following large initial doses in opioid nontolerant patients, or when opioids are given in conjunction with other drugs that depress respiration. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with the sighing pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. This makes overdoses involving drugs with sedative properties and opioids especially dangerous. PRECAUTIONS General: Opioid analgesics impair the mental and/or physical ability required for the performance of potentially dangerous tasks (e.g., driving a car or operating machinery). Patients taking FENTORA should be warned of these dangers and should be counseled accordingly. The use of concomitant CNS active drugs requires special patient care and observation (See WARNINGS). Chronic Pulmonary Disease: Because potent opioids can cause respiratory depression, FENTORA should be titrated with caution in patients with chronic obstructive pulmonary disease or pre-existing medical conditions predisposing them to respiratory depression. In such patients, even normal therapeutic doses of FENTORA may further decrease respiratory drive to the point of respiratory failure. Head Injuries and Increased Intracranial Pressure: FENTORA should only be administered with extreme caution in patients who may be particularly susceptible to the intracranial effects of CO 2 retention such as those with evidence of increased intracranial pressure or impaired consciousness. Opioids may obscure the clinical course of a patient with a head injury and should be used only if clinically warranted. Application Site Reactions: In clinical trials, 10% of all patients exposed to FENTORA reported application site reactions. These reactions ranged from paresthesia to ulceration and bleeding. Application site reactions occurring in 1% of patients were pain (4%), ulcer (3%), and irritation (3%). Application site reactions tended to occur early in treatment, were self-limited and only resulted in treatment discontinuation for 2% of patients. Cardiac Disease: Intravenous fentanyl may produce bradycardia. Therefore, FENTORA should be used with caution in patients with bradyarrhythmias. Hepatic or Renal Disease: Insufficient information exists to make recommendations regarding the use of FENTORA in patients with impaired renal or hepatic function. Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system and mostly eliminated in urine. If the drug is used in these patients, it should be used with caution because of the hepatic metabolism and renal excretion of fentanyl. Information for Patients and Caregivers 1. Patients and their caregivers must be instructed that children, especially small children, exposed to FENTORA are at high risk of FATAL RESPIRATORY DEPRESSION. Patients and their caregivers must be instructed to keep FENTORA tablets out of the reach of children. (See SAFETY AND HANDLING, WARNINGS, and MEDICATION GUIDE for specific patient instructions.) 2. Patients and their caregivers must be provided a Medication Guide each time FENTORA is dispensed because new information may be available. 3. Patients must be instructed not to take FENTORA for acute pain, postoperative pain, pain from injuries, headache, migraine or any other short term pain, even if they have taken other opioid analgesics for these conditions. 4. Patients must be instructed on the meaning of opioid tolerance and that FENTORA is only to be used as a supplemental pain medication for patients with pain requiring around-the-clock opioids, who have developed tolerance to the opioid medication, and who need additional opioid treatment of breakthrough pain episodes. 5. Patients must be instructed that, if they are not taking an opioid medication on a scheduled basis (around-the-clock), they should not take FENTORA. 6. Patients should be instructed that the titration phase is the only period in which they may take more than ONE tablet to achieve a desired dose (e.g., two 100 mcg tablets for a 200 mcg dose). 7. Patients must be instructed that, if the breakthrough pain episode is not relieved after 30 minutes, they may take ONLY ONE ADDITIONAL DOSE OF FENTORA USING THE SAME STRENGTH FOR THAT EPISODE. Thus, patients should take a maximum of two doses of FENTORA for any breakthrough pain episode. 8. Patients must be instructed that they MUST wait at least 4 hours before treating another episode of breakthrough pain with FENTORA. 9. Patients must be instructed NOT to share FENTORA and that sharing FENTORA with anyone else could result in the other individual s death due to overdose. 10. Patients must be aware that FENTORA contains fentanyl which is a strong pain medication similar to hydromorphone, methadone, morphine, oxycodone, and oxymorphone. 11. Patients must be instructed that the active ingredient in FENTORA, fentanyl, is a drug that some people abuse. FENTORA should be taken only by the patient it was prescribed for, and it should be protected from theft or misuse in the work or home environment. 12. Patients must be instructed that FENTORA tablets are not to be swallowed whole; this will reduce the effectiveness of the medication. Tablets are to be placed between the cheek and gum above a molar tooth and allowed to dissolve. After 30 minutes if remnants of the tablet still remain, patients may swallow it with a glass of water. 13. Patients must be cautioned to talk to their doctor if breakthrough pain is not alleviated or worsens after taking FENTORA. 14. Patients must be instructed to use FENTORA exactly as prescribed by their doctor and not to take FENTORA more often than prescribed. 15. Patients must be cautioned that FENTORA can affect a person s ability to perform activities that require a high level of attention (such as driving or using heavy machinery). Patients taking FENTORA should be warned of these dangers and counseled accordingly. 16. Patients must be warned to not combine FENTORA with alcohol, sleep aids, or tranquilizers except by the orders of the prescribing physician, because dangerous additive effects may occur, resulting in serious injury or death. 17. Female patients must be informed that if they become pregnant or plan to become pregnant during treatment with FENTORA, they should ask their doctor about the effects that FENTORA (or any medicine) may have on them and their unborn children. 18. Patients and caregivers must be advised that if they have been receiving treatment with FENTORA and the medicine is no longer needed they should flush any remaining product down the toilet, and if they then need further assistance, contact Cephalon at Laboratory Tests: The effects of FENTORA on laboratory tests have not been evaluated. Drug Interactions: See WARNINGS. Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4); therefore potential interactions may occur when FENTORA is given concurrently with agents that affect CYP3A4 activity. The concomitant use of FENTORA with strong CYP3A4 inhibitors (e.g., ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, and nefazadone) or moderate CYP3A4 inhibitors (e.g., amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, and verapamil) may result in increased fentanyl plasma concentrations, potentially causing serious adverse drug effects including fatal respiratory depression. Patients receiving FENTORA concomitantly with moderate or strong CYP3A4 inhibitors should be carefully monitored for an extended period of time. Dosage increase should be done conservatively. (See PHARMACOKINETICS, Drug Interactions and DOSAGE AND ADMINISTRATION.) Grapefruit and grapefruit juice decrease CYP3A4 activity, increasing blood concentrations of fentanyl, thus should be avoided. Drugs that induce cytochrome P450 3A4 activity may have the opposite effects. Concomitant use of FENTORA with an MAO inhibitor, or within 14 days of discontinuation, is not recommended. Carcinogenesis, Mutagenesis, and Impairment of Fertility: Long-term studies in animals have not been performed to evaluate the carcinogenic potential of fentanyl. Fentanyl citrate was not mutagenic in the in vitro Ames reverse mutation assay in S. tymphimurium or E. coli, or the mouse lymphoma mutagenesis assay. Fentanyl citrate was not clastogenic in the in vivo mouse micronucleus assay. Fentanyl impairs fertility in rats at doses of 30 mcg/kg IV and 160 mcg/kg SC. Conversion to human equivalent doses indicates this is within the range of the human recommended dosing for FENTORA. Pregnancy - Category C: There are no adequate and well-controlled studies in pregnant women. FENTORA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No epidemiological studies of congenital anomalies in infants born to women treated with fentanyl during pregnancy have been reported. Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures characteristic of neonatal abstinence syndrome in newborn infants. Symptoms of neonatal respiratory or neurological depression were no more frequent than expected in most studies of infants born to women treated acutely during labor with intravenous or epidural fentanyl. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl. Fentanyl is embryocidal as evidenced by increased resorptions in pregnant rats at doses of 30 mcg/kg IV or 160 mcg/kg SC. Conversion to human equivalent

8 8 news SATURDAY September 12, 2009 Exit Strategy (continued from page 1) exit strategy? Too often, Schatman says, we rely on old exit strategies, most of which aren t effective. Sedation doesn t reduce withdrawal, alpha 2-agonists can lead to hypotension and other complications, and methadone has what Schatman called very distressing withdrawal symptoms in latter stages. I call methadone the roach motel of opioids, because you can get on, but you can t get off. Worse, according to the latest data (2004), although oxycodone and hydrocodone are prescribed 10 times more than methadone, deaths resulting from those two drugs were only 12% higher than those from methadone abuse. Schatman then outlined the promising initial data around buprenorphine, which indicate that withdrawal symptoms resolve more quickly than with methadone, with less potential for abuse and diversion and similar cost. He was quick to point out the limitations in the literature, however; only eight studies have been conducted to date. Of those eight, only one was performed in the United States, and only two lasted longer than a month. Does [buprenorphine] have a future in pain management? Schatman asked. I think so. Are we ready to call it effective right now? Probably not. The closing portion of the presentation was dedicated to a Washington-state-based effort Schatman is involved in called the Pain Management Options model, or PMO. The model is designed to improve quality of life, it is patient centric, and it is using buprenorphine-assisted detoxification alongside treatment from therapists who are experts in chemical dependency. For more on this model and its promising early results, see the course CD-ROM. In closing, Schatman said that he often hears from pain management specialists that their patients are benefitting from chronic opioid therapy. I simply say, Great. Publish the results. There is no evidence that chronic opioid therapy reduces suffering. Anecdotal evidence is not evidence it s anecdotes. doses indicates this is within the range of the human recommended dosing for FENTORA. Fentanyl citrate was not teratogenic when administered to pregnant animals. Published studies demonstrated that administration of fentanyl (10, 100, or 500 mcg/kg/day) to pregnant rats from day 7 to 21, of their 21 day gestation, via implanted microosmotic minipumps was not teratogenic (the high dose was approximately 3-times the human dose of 1600 mcg per pain episode on a mg/m 2 basis). Intravenous administration of fentanyl (10 or 30 mcg/kg) to pregnant female rats from gestation day 6 to 18, was embryo or fetal toxic, and caused a slightly increased mean delivery time in the 30 mcg/kg/day group, but was not teratogenic. Labor and Delivery: Fentanyl readily passes across the placenta to the fetus; therefore FENTORA is not recommended for analgesia during labor and delivery. Nursing Mothers: Fentanyl is excreted in human milk; therefore FENTORA should not be used in nursing women because of the possibility of sedation and/or respiratory depression in their infants. Symptoms of opioid withdrawal may occur in infants at the cessation of nursing by women using FENTORA. Pediatric Use: See WARNINGS. Geriatric Use: Of the 304 patients with cancer in clinical studies of FENTORA, 69 (23%) were 65 years of age and older. Patients over the age of 65 years tended to titrate to slightly lower doses than younger patients. Patients over the age of 65 years reported a slightly higher frequency for some adverse events specifically vomiting, constipation, and abdominal pain. Therefore, caution should be exercised in individually titrating FENTORA in elderly patients to provide adequate efficacy while minimizing risk. ADVERSE REACTIONS Pre-Marketing Clinical Trial Experience: The safety of FENTORA has been evaluated in 304 opioid tolerant cancer patients with breakthrough pain. The average duration of therapy was 76 days with some patients being treated for over 12 months. The most commonly observed adverse events seen with FENTORA are typical of opioid side effects. Opioid side effects should be expected and managed accordingly. The clinical trials of FENTORA were designed to evaluate safety and efficacy in treating patients with cancer and breakthrough pain; all patients were taking concomitant opioids, such as sustained-release morphine, sustained-release oxycodone or transdermal fentanyl, for their persistent pain. The adverse event data presented here reflect the actual percentage of patients experiencing each adverse effect among patients who received FENTORA for breakthrough pain along with a concomitant opioid for persistent pain. There has been no attempt to correct for concomitant use of other opioids, duration of FENTORA therapy or cancer-related symptoms. Table 5 lists, by maximum dose received, adverse events with an overall frequency of 5% or greater within the total population that occurred during titration. The ability to assign a dose-response relationship to these adverse events is limited by the titration schemes used in these studies. Table 5. Adverse Events Which Occurred During Titration at a Frequency of 5% System Organ Class 100 mcg 200 mcg 400 mcg 600 mcg 800 mcg Total MeDRA preferred (N=45) (N=34) (N=53) (N=56) (N=113) (N=304)* term, n (%) Gastrointestinal disorders Nausea 4 (9) 5 (15) 10 (19) 13 (23) 18 (16) 50 (17) Vomiting 0 2 (6) 2 (4) 7 (13) 3 (3) 14 (5) General disorders and administration site conditions Fatigue 3 (7) 1 (3) 9 (17) 1 (2) 5 (4) 19 (6) Nervous system disorders Dizziness 5 (11) 2 (6) 12 (23) 18 (32) 21 (19) 58 (19) Somnolence 2 (4) 2 (6) 6 (12) 7 (13) 3 (3) 20 (7) Headache 1 (2) 3 (9) 4 (8) 8 (14) 10 (9) 26 (9) * Three hundred and two (302) patients were included in the safety analysis. Table 6 lists, by successful dose, adverse events with an overall frequency of 5% within the total population that occurred after a successful dose had been determined. Table 6. Adverse Events Which Occurred During Long-Term Treatment at a Frequency of 5% System Organ Class 100 mcg 200 mcg 400 mcg 600 mcg 800 mcg Total MeDRA preferred (N=19) (N=31) (N=44) (N=48) (N=58) (N=200) term, n (%) Blood and lymphatic system disorders Anemia 6 (32) 4 (13) 4 (9) 5 (10) 7 (13) 26 (13) Neutropenia 0 2 (6) 1 (2) 4 (8) 4 (7) 11 (6) Gastrointestinal disorders Nausea 8 (42) 5 (16) 14 (32) 13 (27) 17 (31) 57 (29) Vomiting 7 (37) 5 (16) 9 (20) 8 (17) 11 (20) 40 (20) Constipation 5 (26) 4 (13) 5 (11) 4 (8) 6 (11) 24 (12) Diarrhea 3 (16) 0 4 (9) 3 (6) 5 (9) 15 (8) Abdominal pain 2 (11) 1 (3) 4 (9) 7 (15) 4 (7) 18 (9) General disorders and administration site conditions Edema peripheral 6 (32) 5 (16) 4 (9) 5 (10) 3 (5) 23 (12) Asthenia 3 (16) 5 (16) 2 (5) 3 (6) 8 (15) 21 (11) Fatigue 3 (16) 3 (10) 9 (20) 9 (19) 8 (15) 32 (16) Infections and infestations Pneumonia 1 (5) 5 (16) 1 (2) 1 (2) 4 (7) 12 (6) Investigations Weight decreased 1 (5) 1 (3) 3 (7) 2 (4) 6 (11) 13 (7) Metabolism and nutrition disorders Dehydration 4 (21) 0 4 (9) 6 (13) 7 (13) 21 (11) Anorexia 1 (5) 2 (6) 4 (9) 3 (6) 6 (11) 16 (8) Hypokalemia 0 2 (6) 0 1 (2) 8 (15) 11 (6) Musculoskeletal and connective tissue disorders Back pain 2 (11) 0 2 (5) 3 (6) 2 (4) 9 (5) Arthralgia 0 1 (3) 3 (7) 4 (8) 3 (5) 11 (6) Neoplasms benign, malignant and unspecified (including cysts and polyps) Cancer pain 3 (16) 1 (3) 3 (7) 2 (4) 1 (2) 10 (5) Nervous system disorders Dizziness 5 (26) 3 (10) 5 (11) 6 (13) 6 (11) 25 (13) Headache 2 (11) 1 (3) 4 (9) 5 (10) 8 (15) 20 (10) Somnolence 0 1 (3) 4 (9) 4 (8) 8 (15) 17 (9) Psychiatric disorders Confusional state 3 (16) 1 (3) 2 (5) 3 (6) 5 (9) 14 (7) Depression 2 (11) 1 (3) 4 (9) 3 (6) 5 (9) 15 (8) Insomnia 2 (11) 1 (3) 3 (7) 2 (4) 4 (7) 12 (6) Respiratory, thoracic, and mediastinal disorders Cough 1 (5) 1 (3) 2 (5) 4 (8) 5 (9) 13 (7) Dyspnea 1 (5) 6 (19) 0 7 (15) 4 (7) 18 (9) In addition, a small number of patients (n=11) with Grade 1 mucositis were included in clinical trials designed to support the safety of FENTORA. There was no evidence of excess toxicity in this subset of patients. The duration of exposure to FENTORA varied greatly, and included open-label and double-blind studies. The frequencies listed below represent 1% of patients from 3 clinical trials who experienced that event while receiving FENTORA. Events are classified by system organ class. Adverse Events ( 1%): Blood and Lymphatic System Disorders: Anemia, Neutropenia, Thrombocytopenia, Leukopenia; Cardiac Disorders: Tachycardia; Gastrointestinal Disorders: Nausea, Vomiting, Constipation, Abdominal Pain, Diarrhea, Stomatitis, Dry Mouth, Dyspepsia, Upper Abdominal Pain, Abdominal Distension, Dysphagia, Gingival Pain, Stomach Discomfort, Gastroesophageal Reflux Disease, Glossodynia, Mouth Ulceration; General Disorders and Administration Site Conditions: Fatigue, Edema Peripheral, Asthenia, Pyrexia, Application Site Pain, Application Site Ulcer, Chest Pain, Chills, Application Site Irritation, Edema, Mucosal Inflammation, Pain; Hepatobiliary Disorders: Jaundice; Infections and Infestations: Pneumonia, Oral Candidiasis, Urinary Tract Infection, Cellulitis, Nasopharyngitis, Sinusitis, Upper Respiratory Tract Infection, Influenza, Tooth Abscess; Injury, Poisoning and Procedural Complications: Fall, Spinal Compression Fracture; Investigations: Decreased Weight, Decreased Hemoglobin, Increased Blood Glucose, Decreased Hematocrit, Decreased Platelet Count; Metabolism and Nutrition Disorders: Dehydration, Anorexia, Hypokalemia, Decreased Appetite, Hypoalbuminemia, Hypercalcemia, Hypomagnesemia, Hyponatremia, Reduced Oral Intake; Musculoskeletal and Connective Tissue Disorders: Arthralgia, Back Pain, Pain in Extremity, Myalgia, Chest Wall Pain, Muscle Spasms, Neck Pain, Shoulder Pain; Nervous System Disorders: Dizziness, Headache, Somnolence, Hypoesthesia, Dysgeusia, Lethargy, Peripheral Neuropathy, Paresthesia, Balance Disorder, Migraine, Neuropathy; Psychiatric Disorders: Confusional State, Depression, Insomnia, Anxiety, Disorientation, Euphoric Mood, Hallucination, Nervousness; Renal and Urinary Disorders: Renal Failure; Respiratory, Thoracic and Mediastinal Disorders: Dyspnea, Cough, Pharyngolaryngeal Pain, Exertional Dyspnea, Pleural Effusion, Decreased Breathing Sounds, Wheezing; Skin and Subcutaneous Tissue Disorders: Pruritus, Rash, Hyperhidrosis, Cold Sweat; Vascular Disorders: Hypertension, Hypotension, Pallor, Deep Vein Thrombosis OVERDOSAGE Clinical Presentation: The manifestations of FENTORA overdosage are expected to be similar in nature to intravenous fentanyl and other opioids, and are an extension of its pharmacological actions with the most serious significant effect being hypoventilation. General: Immediate management of opioid overdose includes removal of the FENTORA tablet, if still in the mouth, ensuring a patent airway, physical and verbal stimulation of the patient, and assessment of level of consciousness, as well as ventilatory and circulatory status. Treatment of Overdosage in the Opioid Non-Tolerant Person: Ventilatory support should be provided, intravenous access obtained, and naloxone or other opioid antagonists should be employed as clinically indicated. The duration of respiratory depression following overdose may be longer than the effects of the opioid antagonist s action (e.g., the half-life of naloxone ranges from 30 to 81 minutes) and repeated administration may be necessary. Consult the package insert of the individual opioid antagonist for details about such use. Treatment of Overdose in Opioid-Tolerant Patients: Ventilatory support should be provided and intravenous access obtained as clinically indicated. Judicious use of naloxone or another opioid antagonist may be warranted in some instances, but it is associated with the risk of precipitating an acute withdrawal syndrome. General Considerations for Overdose: Management of severe FENTORA overdose includes: securing a patent airway, assisting or controlling ventilation, establishing intravenous access, and GI decontamination by lavage and/or activated charcoal, once the patient s airway is secure. In the presence of hypoventilation or apnea, ventilation should be assisted or controlled and oxygen administered as indicated. Patients with overdose should be carefully observed and appropriately managed until their clinical condition is well controlled. Although muscle rigidity interfering with respiration has not been seen following the use of FENTORA, this is possible with fentanyl and other opioids. If it occurs, it should be managed by the use of assisted or controlled ventilation, by an opioid antagonist, and as a final alternative, by a neuromuscular blocking agent. DOSAGE AND ADMINISTRATION Physicians should individualize treatment using a progressive plan of pain management. Healthcare professionals should follow appropriate pain management principles of careful assessment and ongoing monitoring. (See BOXED WARNING and Dosing.) It is important to minimize the number of strengths available to patients at any time to prevent confusion and possible overdose. Dosing 1. Initial dose a. For opioid-tolerant patients not being converted from Actiq, the initial dose of FENTORA is always 100 mcg. b. For patients being converted from Actiq, prescribers must use the Initial Dosing Recommendations table below (Table 7). The doses of FENTORA in this table are starting doses and not intended to represent equianalgesic doses to Actiq. Patients must be instructed to stop the use of Actiq and dispose of any remaining units. Table 7. Initial Dosing Recommendations for Patients on Actiq Current Actiq Dose (mcg) Initial FENTORA Dose (mcg) mcg tablet mcg tablet mcg tablet mcg tablet x 200 mcg tablets x 200 mcg tablets c. For patients converting from Actiq doses equal to or greater than 600 mcg, titration should be initiated with the 200 mcg FENTORA tablet and should proceed using multiples of this tablet strength. d. In cases where the breakthrough pain episode is not relieved after 30 minutes, patients may take ONLY ONE additional dose using the same strength for that episode. Thus patients should take a maximum of two doses of FENTORA for any episode of breakthrough pain. e. Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with FENTORA. 2. Titration a. From an initial dose, patients should be closely followed by the prescriber and the dosage strength changed until the patient reaches a dose that provides adequate analgesia with tolerable side effects. Patients should record their use of FENTORA over several episodes of breakthrough pain and discuss their experience with their physician to determine if a dosage adjustment is warranted. b. Patients whose initial dose is 100 mcg and who need to titrate to a higher dose, can be instructed to use two 100-mcg tablets (one on each side of the mouth in the buccal cavity) with their next breakthrough pain episode. If this dosage is not successful, the patient may be instructed to place two 100-mcg tablets on each side of the mouth in the buccal cavity (total of four 100 mcg tablets). Titrate using multiples of the 200-mcg FENTORA tablet for doses above 400 mcg (600 mcg and 800 mcg) Note: Do not use more than 4 tablets simultaneously. c. In cases where the breakthrough pain episode is not relieved after 30 minutes, patients may take ONLY ONE additional dose of the same strength for that episode. Thus patients should take a maximum of two doses of FENTORA for any breakthrough pain episode. During titration, one dose of FENTORA may include administration of 1 to 4 tablets of the same dosage strength (100 mcg or 200 mcg). d. Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with FENTORA. To reduce the risk of overdose during titration, patients should have only one strength of FENTORA tablets available at any one time. e. Patients should be strongly encouraged to use all of their FENTORA tablets of one strength prior to being prescribed the next strength. If this is not practical, unused FENTORA should be disposed of safely. (See DISPOSAL OF FENTORA.) Dispose of any unopened FENTORA tablets remaining from a prescription as soon as they are no longer needed. 3. Maintenance Dosing a. Once titrated to an effective dose, patients should generally use only ONE FENTORA tablet of the appropriate strength per breakthrough pain episode. b. On occasion when the breakthrough pain episode is not relieved after 30 minutes, patients may take ONLY ONE additional dose using the same strength for that episode. c. Patients MUST wait at least 4 hours before treating another episode of breakthrough pain with FENTORA. d. Dosage adjustment of FENTORA may be required in some patients in order to continue to provide adequate relief of breakthrough pain. Generally, the FENTORA dose should be increased only when a single administration of the current dose fails to adequately treat the breakthrough pain episode for several consecutive episodes. If the patient experiences greater than four breakthrough pain episodes per day, the dose of the maintenance (aroundthe-clock) opioid used for persistent pain should be re-evaluated. Patients with hepatic and/or renal impairment: Caution should be exercised for patients with hepatic and/or renal impairment, and the lowest possible dose should be used in these patients. (See PRECAUTIONS.) Patients receiving CYP3A4 inhibitors: Particular caution should be exercised for patients receiving CYP3A4 inhibitors, and the lowest possible dose should be used in these patients. (See PRECAUTIONS.)

9 Red Rock Casino, Resort, and Spa Las Vegas, NV news 9 PAINWeek 2009 Snapshots Patients with mucositis: No dose adjustment appears necessary in patients with Grade 1 mucositis. The safety and efficacy of FENTORA when used in patients with mucositis more severe than Grade 1 have not been studied. Opening the Blister Package 1. Patients should be instructed not to open the blister until ready to administer FENTORA. 2. A single blister unit should be separated from the blister card by bending and tearing apart at the perforations. 3. The blister unit should then be bent along the line where indicated. 4. The blister backing should then be peeled back to expose the tablet. Patients should NOT attempt to push the tablet through the blister as this may cause damage to the tablet. 5. The tablet should not be stored once it has been removed from the blister package as the tablet integrity may be compromised and, more importantly, because this increases the risk of accidental exposure to the tablet. Tablet Administration: Once the tablet is removed from the blister unit, the patient should immediately place the entire FENTORA tablet in the buccal cavity (above a rear molar, between the upper cheek and gum). Patients should not attempt to split the tablet. The FENTORA tablet should not be sucked, chewed or swallowed, as this will result in lower plasma concentrations than when taken as directed. The FENTORA tablet should be left between the cheek and gum until it has disintegrated, which usually takes approximately minutes. After 30 minutes, if remnants from the FENTORA tablet remain, they may be swallowed with a glass of water. It is recommended that patients alternate sides of the mouth when administering subsequent doses of FENTORA. SAFETY AND HANDLING FENTORA is supplied in individually sealed, child-resistant blister packages. The amount of fentanyl contained in FENTORA can be fatal to a child. Patients and their caregivers must be instructed to keep FENTORA out of the reach of children. (See BOXED WARNING, WARNINGS, PRECAUTIONS, and MEDICATION GUIDE.) Store at 20-25ºC (68-77ºF) with excursions permitted between 15 and 30 C (59 to 86 F) until ready to use. (See USP Controlled Room Temperature.) FENTORA should be protected from freezing and moisture. Do not use if the blister package has been tampered with. DISPOSAL OF FENTORA Patients and members of their household must be advised to dispose of any tablets remaining from a prescription as soon as they are no longer needed. Information is available in Information for Patients and Caregivers and in the Medication Guide. If additional assistance is required, referral to the Cephalon 800# ( ) should be made. To dispose of unused FENTORA, remove FENTORA tablets from blister packages and flush down the toilet. Do not flush FENTORA blister packages or cartons down the toilet. If you need additional assistance with disposal of FENTORA, call Cephalon, Inc., at HOW SUPPLIED Each carton contains 7 blister cards with 4 white tablets in each card. The blisters are child resistant, encased in peelable foil, and provide protection from moisture. Each tablet is debossed on one side with, and the other side of each dosage strength is uniquely identified by the debossing on the tablet. The dosage strength of each tablet is marked on the tablet, the blister package and the carton. See blister package and carton for product information. Note: Carton/blister package colors are a secondary aid in product identification. Please be sure to confirm the printed dosage before dispensing. Manufactured for: Cephalon, Inc. Frazer, PA By: CIMA LABS, INC. Cephalon, Inc Valley View Road and 4745 Wiley Post Way Eden Prairie, MN Salt Lake City, UT U. S. Patent Nos. 6,200,604 and 6,974,590 Printed in USA FENT Cephalon, Inc. All rights reserved. Evaluations and CE Certificates are now going green! All evaluations can now be completed online. Log on to the online Conference Evaluation System at or click on the Request CE Credit logo at the Cybercafé. You may complete your evaluations using your laptop anywhere in the conference area, including your room, or at an available computer in the Cybercafé. You may also complete evaluations after the conference until September 30, Instructions 1. Enter in your Numeric Badge Number (located below your bar code on your name badge) 2. Type the Last Name you used to register (this is not case-sensitive but should be identical to the name printed on your name badge; don t forget to include hyphens) 3. Evaluate PAINWeek overall and specific courses that you attended. To evaluate a specific course, click Evaluate Attended Course, then scroll to find the course and click evaluate next to the course code and name. 4. A green checkmark ( ) indicates that you have completed the evaluation 5. Once you have completed an evaluation, you can select your type of CE certificate based on your professional credentials. Click Get Certificate to view, save, print, or a PDF certificate to yourself. 6. You have until Wednesday, September 30, 2009, to complete your evaluations and to receive CE/CME credit. No requests for credit will be accepted after this date. Helpful Hints ahs 0080 green.eval.v1 1. You can log on to the system as many times as necessary. We do recommend completing evaluations as soon as you complete a course to keep the information fresh in your memory. 2. We also recommend that you do not wait until the deadline to complete your evaluations. No requests for credit will be accepted after this deadline.

10 10 news SATURDAY September 12, 2009 Net Guide During or after the conference, check out the informative sites below, which complement the tracks presented at today s PAINWeek sessions. Pain and Chemical Dependency Online CME Medical Heroin Works to Beat Opioid Addiction Credits: 0.25 Fee: None Expires: August 19, 2010 Based on research findings that show injectable diacetylmorphine (the active ingredient in heroin) to be an effective alternative to oral methadone for the treatment of opioid addiction, this CME program reviews the study results and the relevance and significance of these results in the broader context of clinical care. Participants will learn about the use of diacetylmorphine used in Europe but not legally available in the US as a reserve for patients who don t respond to standard treatment with methadone for opioid addiction. Obtain your CME credit for this activity at: Newswatch Majority of Chronic Pain Patients Improperly Use Prescribed Medications A majority of patients suffering from chronic pain who were prescribed opioids are unlikely to be taking their medicine in a manner consistent with their prescribed regimen, according to the results of a new study from Ameritox, which provides medication monitoring solutions, offering specialized laboratory testing and reporting services. According to the researchers, among the patients taking chronic opioid therapy who were given urine toxicology tests, 8% of patients had no detectable level of their prescribed medication (typically an opioid or benzodiazepine type drug); 27% had a drug level higher than expected; 15% had a drug level lower than expected; 11% had major illicit drugs such as cocaine or methamphetamines detected in their urine; and 29% had a medication in their system that the doctor was likely unaware of. In a summary of the findings, the researchers said that urine toxicology testing showed that only 25% of the patients were definitively taking their medications as prescribed, with no evidence of illicit drug use or misuse of prescribed drugs. Read the full story online at: From the Literature Universal Precautions Revisited: Managing the Inherited Pain Patient Journal: Emergency Medicine (July/August 2009) Authors: Gourlay D, Heit H Purpose: To explore the application of a Universal Precautions approach to manage the care of patients with chronic pain who no longer have an appropriate source of the medications upon which they have become physically dependent so-called inherited pain patients. Results: Universal Precautions as a concept should be based upon mutual trust and respect between patient and practitioner, both of whom should be committed to setting and achieving realistic goals in both cancer and noncancer pain patients. Access the abstract and full article online at: com/muwsoj. Rheumatology Online CME Evaluation of Symptomatic Slow-Acting Drugs in Osteoarthritis Using the GRADE System Credits: 0.75 Fee: None Expires: February 4, 2010 Complete this CME course for a review of the joints that are commonly affected by osteoarthritis (OA), the components of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system for determining evidence quality, and symptomatic slow-acting drugs for treating OA. Registration with Medscape is required in order to complete and obtain credit for this activity. Visit to participate in this course. Medical Websites HCPLive: Rheumatoid Arthritis Resource Center Access educational materials, conference posters, videos, event information, nurse modules, and more, all focused on rheumatoid arthritis and all in one place, the HCPLive network. Keep up with conferences and events, as well as all the latest rheumatoid arthritis news at com/my5erm. National Fibromyalgia Research Association The National Fibromyalgia Research Association aims to be the premier source for what is new in the field of fibromyalgia research and education. Visit the Central Nervous System section to access comparative symptom charts, articles on spinal cord measurement protocols, and a radiologic guide to MRI interpretation. Numerous study abstracts can be found here as well. Click on Treatment Options to view information on medications, vitamins, exercises, neurological exams, and sleep therapies. View the What s New section to see the most recent news and updates made on the site. Access the site at: Musculoskeletal and Connective Tissue Disorders: Merck Manual for Professionals Among the numerous topics covered in this section of the Merck Manual are juvenile idiopathic arthritis, neurogenic arthropathy, rheumatoid arthritis, and osteoporosis. For each topic, diagnosis and treatment are thoroughly reviewed; some topics also include coverage of symptoms and signs, pathophysiology, prognosis, etiology, classification, prevention, and available medications. Throughout, key phrases are hyperlinked to information on that topic, and drug names are linked to a respective drug monograph, making for a virtually endless learning experience. Through this site, you can also buy the hard-copy book, download the manual for your PDA, and listen to podcasts from the latest edition. Review the entire section of the manual at com/mfdk3z. Complementary and Alternative Medicine Treating Cancer Pain The Pain Management section of Cancer Treatment Centers of America s (CTCA) Complementary Cancer Therapies pages features a text and video overview of cancer pain management, a discussion of the dimensions of cancer pain, and lays out both the pain management techniques used at CTCA and their general treatment plan. Links to patient education resources are also accessible. The Continuum Center for Health & Healing (CHH) Upon selecting a disease from CHH s list of health conditions site visitors are presented with a listing of complementary and alternative therapies indicated for treatment of the condition along with links to the body of scientific evidence that validated it. Sign up for CHH s quarterly newsletter CenterPoint to keep abreast of developments at the Center and in Integrative Medicine. Integrative Approach to Pain This archived webcast, moderated by Benjamin Kligler, MD, MPH, Associate Professor of Family Medicine, Albert Einstein College of Medicine and Research Director, Continuum Center for Health and Healing, describes an integrative approach to pain management involving nutritional medicine, herbs and supplements, mind-body medicine, manual therapies, and East Asian medicine. A warning: the presentation runs a lengthy one hour and 24 minutes.

11 Your Partner in Pain Medication Monitoring Monitoring your patients for proper drug use is more important now than it has ever been before. ATN s innovative approach shares the testing and the reimbursement. Our program helps protect your patients and your practice. STEP ONE: Test your patients instantly for a broad spectrum of drugs. Purchase and use the CLIA Waived ATN FasTox 12 to check your patients for the proper use of prescribed drugs and the use of illegal drugs. Use the ATN FasTox 12 without meeting complex CLIA laboratory regulations. Don t risk violation of Federal lab regulations by using a non-clia waived test. Don t risk violation of Federal lab inducement (Anti-Kickback) laws by using FREE tests given to you by other labs. Bill the provider directly using CPT code for each of the 12 drug classes tested by the ATN FasTox 12 and receive the reimbursement. STEP TWO: Use ATN s comprehensive laboratory testing for the complete picture You decide which patient samples need additional testing at Advanced Toxicology Network (ATN). Stop by booth # 109 and talk with us. ATN provides additional screening for drugs not available on the ATN FasTox 12 and GC/MS quantitative results from our SAMHSA and CLIA federally certified laboratory. Get your faster results from ATN by utilizing our unique logistics advantage of being located next to the FedEx super hub in Memphis. Receive results via various reporting options: FAX, , direct download or from our secure web site. ATN will bill for testing performed at our lab: Medicare, Medicaid, 3 rd party & Self-Pays. For all testing, ATN will provide you the appropriate CPT codes. Advanced Toxicology Network (ATN) is a CLIA licensed and SAMHSA certified laboratory by the Federal Government. ATN is one of the largest drug testing laboratories in the U.S. ATN offers the CLIA Waived ATN FasTox 12 for in office testing and complete in-house laboratory testing services. Expect More From Your Laboratory! For additional information contact ATN Sales at or russ_smith@atnlabs.com

12 12 news SATURDAY September 12, 2009 PREVIEW Oral Presentations These six abstracts have been selected for podium presentations today at 9:00am in Veranda DE. Consult your PAINWeek 2009 Abstracts program for complete writeups of the abstracts selected for oral presentation, along with abstracts of all other posters presented at PAINWeek So many publications, one online destination For busy physicians, every minute counts. MDNG: Pain Management Edition s robust new Web portal, can help you keep abreast of the latest news and research by quickly and efficiently putting a wealth of relevant, quality information at your disposal. Registered users can access full-text articles dating back to January 2007, start a discussion in an interactive forum, and access pain medicine-related information from the journal s many sister publications, including The American Journal of Managed Care and Pharmacy Times. HCPLive is the pre-eminent online source for physicians and other healthcare professionals who are looking for information, tools, and techniques to improve patient care. The site s unique content is organized by specialty, publication, and audience, under one customizable network, offering readers quality content in a streamlined package. HCPLive is the most comprehensive portal on the Web for today s busy healthcare professional. Booth 214 B R I N G I N G H E A L T H C A R E T E C H N O L O G Y I N T O P R A C T I C E Fibromyalgia: Identifying Differences in Diagnosis and Impact between Men and Women Presented by Michelle M. Burke, CNP, MS, RN, BC; Connie A. Luedtke, MA, RN, BC; and Jeffrey M. Thompson, MD, this descriptive comparative study was conducted to determine if a difference existed in the number of associated symptoms and tender points between men and women with fibromyalgia and to determine whether the impact of this diagnosis on functioning and quality of life differs by gender as measured by the Fibromyalgia Impact Questionnaire (FIQ). The authors report that men and women differed in the number and location of tender points and in the incidence of several associated symptoms. They did not differ, however, in the rank order of the top four most common associated symptoms, or in the impact of fibromyalgia on their lives as measured by the FIQ. Efficacy and Safety of Tapentadol ER for Chronic Low Back Pain Robert Buynak, MD, FACP; Douglas Y. Shapiro, MD, PhD; Akiko Akamoto, ScD; et al. will present the results of their study that evaluated the efficacy and safety of tapentadol extended release (ER) for the management of moderate to severe chronic low back pain. They will report that Tapentadol ER ( mg bid) effectively relieved moderate to severe chronic low back pain compared with placebo. A Randomized, Double-blind, Placebo-controlled Study of OROS Hydromorphone Extended-release in Opioid-tolerant Patients with Chronic Low Back Pain Martin Hale, MD; Richard Rauk, MD; Arifulla Khan, MD; et al., will present the results of a study that evaluated the safety, efficacy, and tolerability of once-daily OROS hydromorphone extended release (ER) for moderate-to-severe chronic low back pain in opioidtolerant patients. The authors reported that once-daily OROS hydromorphone ER was safe, effective, and well tolerated in this patient population, with treatment-related adverse events consistent with that of IR hydromorphone and oral opioids in general. Quality of Life in Patients Managing Chronic Pain with Opioids: The Opioid Utilization Study (OPUS) Based on an abstract submitted by Steven Stanos, DO; Charles E. Argoff, MD; R. Amy Puenpatom, PhD, et al., this presentation will report on baseline quality of life measures for patients enrolled in the Opioid Utilization Study, which was designed to characterize the utilization of opioid therapy in patients with chronic noncancer pain and to analyze quality of life measures, economic patient-reported outcomes, and healthcare resource utilization. The presentation will review results from the study that indicate that patients managing chronic noncancer pain with opioids have impaired quality of life, particularly patients who are women, nonwhite, and have low income. Vol. 2, No. 2 March/April 09 Invisible No More Fibromyalgia patients and advocates fight for recognition What are the cornerstone effective pain manageme The Pacemaker for P Breakthrou breakthroug Alw Internet lis Relative Bioavailability of ALO-01 (Morphine Sulfate and Naltrexone Hydrochloride) Extended Release Capsules (Embeda ) Compared with Morphine Sulfate This presentation, based on an abstract submitted by Marsha Stanton, PhD, RN; Paul F. Cavanaugh, Jr, PhD; Franklin Johnson, MS; and Beatrice Setnick, PhD, will discuss results of studies performed to assess the bioavailability of morphine in ALO-01 relative to a marketed extended-release morphine sulfate (ERMS) formulation without naltrexone (Kadian ) after single-dose administration and at steady state. The authors reported that single doses of ALO-01 or ERMS are bioequivalent, and also that mean pain scores and mean plasma morphine steady-state exposures were not statistically different between the two treatments. PainACTION.com: An Interactive Self-management Website for Chronic Pain Patients Don t miss this presentation, based on an abstract submitted by Kevin L. Zacharoff, MD; Emil Chiauzzi, PhD; Synne Wing Venuti, MSW; and Pravin Pant, BA. It will describe the formative research and development of painaction.com, an interactive website for chronic pain patients. Although complete study results will not be available until later this year, the presenters will describe the designs of the field trials to test the efficacy of the website in terms of helping reduce participant s pain, increase their physical functioning, reduce psychological distress, and increase their use of positive coping strategies. Part of the

13 Red Rock Casino, Resort, and Spa Las Vegas, NV news 13 Fibromyalgia can be overwhelming Savella is a selective serotonin and norepinephrine reuptake inhibitor (SNRI), similar to some drugs used for the treatment of depression and other psychiatric disorders. Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of such drugs in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on Savella should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior, especially during the initial few months of drug therapy or at times of dose changes, either increases or decreases. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Savella is not approved for use in the treatment of major depressive disorder. Savella is not approved for use in pediatric patients. Please see additional Important Safety Information and brief summary of Prescribing Information on the following pages.

14 Contraindications Savella is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs) concomitantly or within 14 days of discontinuing treatment with an MAOI. There have been reports of serious, sometimes fatal, reactions in patients started on an MAOI who were receiving or had recently discontinued a serotonin reuptake inhibitor. At least 5 days should be allowed after stopping Savella before starting an MAOI. Savella is contraindicated in patients with uncontrolled narrow-angle glaucoma and should be used with caution in patients with controlled narrow-angle glaucoma. In clinical trials, Savella was associated with an increased risk of mydriasis. Warnings and Precautions Prescriptions for Savella should be written for the smallest quantity of tablets, consistent with good patient management, in order to reduce the risk of overdose. Development of a potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions have been reported with SSRIs and SNRIs alone, including Savella, but particularly with concomitant use of serotonergic drugs (including triptans), drugs that impair metabolism of serotonin (including MAOIs), or antipsychotics or other dopamine antagonists. The management of these reactions should include immediate discontinuation of Savella and the concomitant agent and supportive symptomatic treatment. The concomitant use of Savella with serotonin precursors is not recommended. SNRIs, including Savella, have been associated with cardiovascular effects, including cases of elevated blood pressure, requiring immediate treatment. In clinical trials, sustained increases in systolic and diastolic blood pressure occurred more frequently in Savella-treated patients compared to placebo. Among patients who were non-hypertensive at baseline, approximately twice as many patients receiving Savella, vs placebo, became hypertensive at the end of the study. Clinically signifi cant increases in pulse ( 20 bpm) occurred more frequently in Savella-treated than placebo-treated patients. Blood pressure and heart rate should be monitored prior to initiating treatment with Savella and periodically throughout treatment. Pre-existing hypertension, tachyarrhythmias, and other cardiac diseases should be treated before starting therapy with Savella. Savella should be used with caution in patients with signifi cant hypertension or cardiac disease. Concomitant use of Savella with drugs that increase blood pressure and pulse has not been evaluated, and such combinations should be used with caution. For patients who experience a sustained increase in blood pressure or heart rate while receiving Savella, either dose reduction or discontinuation should be considered. Savella should be prescribed with caution in patients with a history of seizure disorder or mania. Savella has been associated with mild elevations of ALT and AST (1 to 3 times the upper limit of normal). Rarely, reports of serious liver injury, including fulminant hepatitis, have been reported in patients treated with milnacipran. Savella should be Please see Boxed Warning on previous page and brief summary of Prescribing Information on the following pages.

15 New for the management of fi bromyalgia Savella relieves symptoms of fibromyalgia Delivers simultaneous improvements on 3 measures of fi bromyalgia 1 Pain reduction Improvement in patient global fi bromyalgia assessment Improvement in physical function Decrease in pain as early as week 1 of treatment with a stable dose in patients who reported global improvement 1 Low potential for pharmacokinetic drug-drug interactions 1 Clinically important interactions may occur with lithium, epinephrine and norepinephrine, serotonergic drugs, digoxin, clonidine, clomipramine, CNS-active drugs, and MAOIs A dual reuptake inhibitor that blocks the uptake of norepinephrine over serotonin with approximately 3 times greater potency in vitro 1 * *The clinical signifi cance of in vitro data is unknown. discontinued in patients who develop jaundice or other evidence of liver dysfunction and should not be resumed unless another cause can be established. As with other SNRIs and SSRIs, withdrawal symptoms have been observed following discontinuation of milnacipran. A gradual dose reduction is recommended. Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Savella. Elderly patients may be at greater risk. Discontinuation should be considered for patients with symptomatic hyponatremia. SSRIs and SNRIs, including Savella, may increase the risk of bleeding events. Patients should be cautioned regarding the risk of bleeding associated with concomitant use of Savella and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation. Savella can affect urethral resistance and micturition. Caution is advised in the use of Savella in patients with a history of dysuria, notably in male patients with a history of obstructive uropathies as these patients may experience higher rates of genitourinary adverse events. Savella should ordinarily not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease. Use in Specific Populations There are no adequate and well-controlled studies in pregnant women. Savella should be used during pregnancy only if the potential benefi t justifi es the potential risk to the fetus. Adverse Reactions In clinical trials, the most frequently occurring adverse reaction was nausea (37% vs 20% for placebo). The most commonly occurring adverse reactions ( 5% and greater than placebo) were headache (18% vs 14%), constipation (16% vs 4%), dizziness (10% vs 6%), insomnia (12% vs 10%), hot fl ush (12% vs 2%), hyperhidrosis (9% vs 2%), vomiting (7% vs 2%), palpitations (7% vs 2%), heart rate increased (6% vs 1%), dry mouth (5% vs 2%), and hypertension (5% vs 2%). For Full Prescribing Information, visit Reference: 1. Savella (milnacipran HCl) prescribing information. Forest Pharmaceuticals, Inc. St Louis, MO. Licensed from Pierre Fabre and Cypress Bioscience, Inc Forest Laboratories, Inc TR1 08/09

16 Savella (milnacipran HCl) Tablets Rx Only Brief Summary of Full Prescribing Information Initial U.S. Approval: 2009 WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS Savella is a selective serotonin and norepinephrine reuptake inhibitor (SNRI), similar to some drugs used for the treatment of depression and other psychiatric disorders. Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of such drugs in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on Savella should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Savella is not approved for use in the treatment of major depressive disorder. Savella is not approved for use in pediatric patients [see Warnings and Precautions, Use in Specific Populations]. INDICATIONS AND USAGE: Savella is indicated for the management of fibromyalgia. Savella is not approved for use in pediatric patients [see Use in Specific Populations]. CONTRAINDICATIONS: Monoamine Oxidase Inhibitors-Concomitant use of Savella in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated. In patients receiving a serotonin reuptake inhibitor in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued serotonin reuptake inhibitors and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. The effects of combined use of Savella and MAOIs have not been evaluated in humans. Therefore, it is recommended that Savella should not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 5 days should be allowed after stopping Savella before starting an MAOI [see Dosage and Administration, Warnings and Precautions]. Uncontrolled Narrow-Angle Glaucoma-In clinical trials, Savella was associated with an increased risk of mydriasis. Mydriasis has been reported with other dual reuptake inhibitors of norepinephrine and serotonin; therefore, do not use Savella in patients with uncontrolled narrow-angle glaucoma. WARNINGS AND PRECAUTIONS: Suicide Risk-Savella is a selective serotonin and norepinephrine re-uptake inhibitor (SNRI), similar to some drugs used for the treatment of depression and other psychiatric disorders. Patients, both adult and pediatric, with depression or other psychiatric disorders may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking these medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants, including drugs that inhibit the reuptake of norepinephrine and/or serotonin, may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. In the placebo-controlled clinical trials of adults with fibromyalgia, among the patients who had a history of depression at treatment initiation, the incidence of suicidal ideation was 0.5% in patients treated with placebo, 0% in patients treated with Savella 100 mg/day, and 1.3% in patients treated with Savella 200 mg/day. No suicides occurred in the short-term or longer-term (up to 1 year) fibromyalgia trials. Pooled analyses of short-term placebo-controlled trials of drugs used to treat depression (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with these drugs compared to placebo in adults beyond age 24; there was a reduction in suicidality risk with antidepressants compared to placebo in adults age 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 drugs used to treat depression in over 4400 patients. The pooled analyses of placebocontrolled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug versus placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1. Risk Differences (Drug Placebo) in the number of Cases of Suicidality, per 1000 patients treated Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated < additional cases additional cases Decreases Compared to Placebo fewer case 65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of anti-depressants can delay the recurrence of depression. All patients being treated with drugs inhibiting the reuptake of norepinephrine and/or serotonin for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, have been reported in adult and pediatric patients being treated with drugs inhibiting the reuptake of norepinephrine and/or serotonin for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who may experience worsening depressive symptoms, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe or abrupt in onset, or were not part of the patient s presenting symptoms. If the decision has been made to discontinue treatment due to worsening depressive symptoms or emergent suicidality, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can produce withdrawal symptoms [see Dosage and Administration Recommended Dosing, Dosage Discontinuing Savella, and Warnings and Precautions Discontinuation of Treatment with Savella]. Families and caregivers of patients being treated with drugs inhibiting the reuptake of norepinephrine and/or serotonin for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Savella should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-Like Reactions-The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including Savella, but particularly with concomitant use of serotonergic drugs (including triptans), with drugs which impair metabolism of serotonin (including MAOIs) or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) [see Drug Interactions]. Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms. The concomitant use of Savella with MAOIs is contraindicated [see Contraindications]. If concomitant treatment of Savella with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Drug Interactions]. The concomitant use of Savella with serotonin precursors (such as tryptophan) is not recommended [see Drug Interactions]. Treatment with Savella and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Effects on Blood Pressure-Inhibition of the reuptake of norepinephrine (NE) and serotonin (5-HT) can lead to cardiovascular effects. SNRIs, including Savella, have been associated with reports of increase in blood pressure. In a double-blind, placebo-controlled clinical pharmacology study in healthy subjects designed to evaluate the effects of milnacipran on various parameters, including blood pressure at supratherapeutic doses, there was evidence of mean increases in supine blood pressure at doses up to 300 mg twice daily (600 mg/day). At the highest 300 mg twice daily dose, the mean increase in systolic blood pressure was up to 8.1 mm Hg for the placebo group and up to 10.0 mm Hg for the Savella treated group over the 12 hour steady state dosing interval. The corresponding mean increase in diastolic blood pressure over this interval was up to 4.6 mm Hg for placebo and up to 11.5 mm Hg for the Savella treated group. In the 3-month placebo-controlled fibromyalgia clinical trials, Savella treatment was associated with mean increases of up to 3.1 mm Hg in systolic blood pressure (SBP) and diastolic blood pressure (DBP) [see Adverse Reactions]. In the placebo-controlled trials, among fibromyalgia patients who were non-hypertensive at baseline, approximately twice as many patients in the Savella treatment arms became hypertensive at the end of the study (SBP 140 mmhg or DBP 90 mmhg) compared with the placebo patients: 7.2% of patients in the placebo arm versus 19.5% of patients treated with Savella 100 mg/day and 16.6% of patients treated with Savella 200 mg/day. Among patients who met systolic criteria for pre-hypertension at baseline (SBP mmhg), more patients became hypertensive at the end of the study in the Savella treatment arms than placebo: 9% of patients in the placebo arm versus 14% in both the Savella 100 mg/day and the Savella 200 mg/day treatment arms. Among fibromyalgia patients who were hypertensive at baseline, more patients in the Savella treatment arms had a >15 mmhg increase in SBP than placebo at the end of the study: 1% of patients in the placebo arm versus 7% in the Savella 100 mg/day and 2% in the Savella 200 mg/day treatment arms. Similarly, more patients who were hypertensive at baseline and were treated with Savella had DBP increases > 10 mmhg than placebo at the end of study: 3% of patients in the placebo arm versus 8% in the Savella 100 mg/day and 6% in the Savella 200 mg/day treatment arms. Sustained increases in SBP (increase of 15 mmhg on three consecutive post-baseline visits) occurred in 2% of placebo patients versus 9% of patients receiving Savella 100 mg/day and 6% of patients receiving Savella 200 mg/day. Sustained increases in DBP (increase of 10 mmhg on 3 consecutive post-baseline visits) occurred in 4% of patients receiving placebo versus 13% of patients receiving Savella 100 mg/day and 10% of patients receiving Savella 200 mg/day. Sustained increases in blood pressure could have adverse consequences. Cases of elevated blood pressure requiring immediate treatment have been reported. Concomitant use of Savella with drugs that increase blood pressure and pulse has not been evaluated and such combinations should be used with caution [see Drug Interactions]. Effects of Savella on blood pressure in patients with significant hypertension or cardiac disease have not been systematically evaluated. Savella should be used with caution in these patients. Blood pressure should be measured prior to initiating treatment and periodically measured throughout Savella treatment. Pre-existing hypertension and other cardiovascular disease should be treated before starting therapy with Savella. For patients who experience a sustained increase in blood pressure while receiving Savella, either dose reduction or discontinuation should be considered. Effects on Heart Rate-SNRIs have been associated with reports of increase in heart rate. In clinical trials, relative to placebo, Savella treatment was associated with mean increases in pulse rate of approximately 7 to 8 beats per minute [see Adverse Reactions]. Increases in pulse 20 bpm occurred more frequently in Savella-treated patients when compared to placebo: 0.3% in the placebo arm versus 8% in the Savella 100 mg/day and 8% in the 200 mg/day treatment arms. The effect of Savella on heart rate did not appear to increase with increasing dose. Savella has not been systematically evaluated in patients with a cardiac rhythm disorder. Heart rate should be measured prior to initiating treatment and periodically measured throughout Savella treatment. Pre-existing tachyarrhythmias and other cardiac disease should be treated before starting therapy with Savella. For patients who experience a sustained increase in heart rate while receiving Savella, either dose reduction or discontinuation should be considered. Seizures-Savella has not been systematically evaluated in patients with a seizure disorder. In clinical trials evaluating Savella in patients with fibromyalgia, seizures/convulsions have not been reported. However, seizures have been reported infrequently in patients treated with Savella for disorders other than fibromyalgia. Savella should be prescribed with care in patients with a history of a seizure disorder. Hepatotoxicity-In the placebo-controlled fibromyalgia trials, increases in the number of patients treated with Savella with mild elevations of ALT or AST (1-3 times the upper limit of normal, ULN) were observed. Increases in ALT were more frequently observed in the patients treated with Savella 100 mg/day (6%) and Savella 200 mg/day (7%), compared to the patients treated with placebo (3%). One patient receiving Savella 100 mg/day (0.2%) had an increase in ALT greater than 5 times the upper limit of normal but did not exceed 10 times the upper limit of normal. Increases in AST were more frequently observed in the patients treated with Savella 100 mg/day (3%) and Savella 200 mg/day (5%) compared to the patients treated with placebo (2%). The increases of bilirubin observed in the fibromyalgia clinical trials were not clinically significant. No case met the criteria of elevated ALT > 3x ULN and associated with an increase in bilirubin 2x ULN. There have been cases of increased liver enzymes and reports of severe liver injury, including fulminant hepatitis with milnacipran from foreign postmarketing experience. In the cases of severe liver injury there were significant underlying clinical conditions and/or the use of multiple concomitant medications. Because of underreporting, it is impossible to provide an accurate estimate of the true incidence of these reactions. Savella should be discontinued in patients who develop jaundice or other evidence of liver dysfunction. Treatment with Savella should not be resumed unless another cause can be established. Savella should ordinarily not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease. Discontinuation of Treatment with Savella-Withdrawal symptoms have been observed in clinical trials following discontinuation of milnacipran, as with other SNRIs and SSRIs. During marketing of milnacipran, and other SNRIs and SSRIs, there have been spontaneous reports of adverse events indicative of withdrawal and physical dependence occurring upon discontinuation of these drugs, particularly when discontinuation is abrupt. The adverse events include the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe. Patients should be monitored for these symptoms when discontinuing treatment with Savella. Savella should be tapered and not abruptly discontinued after extended use. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate [see Dosage and Administration]. Hyponatremia-Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Savella. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/l have been reported. Elderly patients may be at greater risk of developing hyponatremia with SNRIs, SSRIs, or Savella. Also, patients taking diuretics or who are otherwise volume-depleted may be at greater risk [see Geriatric Use]. Discontinuation of Savella should be considered in patients with symptomatic hyponatremia. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. Abnormal Bleeding-SSRIs and SNRIs, including Savella, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of Savella and NSAIDs, aspirin, or other drugs that affect coagulation. Activation of Mania-No activation of mania or hypomania was reported in the clinical trials evaluating effects of Savella in patients with fibromyalgia. However those clinical trials excluded patients with current major depressive episode. Activation of mania and hypomania have been reported in patients with mood disorders who were treated with other similar drugs for major depressive disorder. As with these other agents, Savella should be used cautiously in patients with a history of mania. Patients with a History of Dysuria-Because of their noradrenergic effect, SNRIs including Savella, can affect urethral resistance and micturition. In the controlled fibromyalgia trials, dysuria occurred more frequently in patients treated with Savella (1%) than in placebo-treated patients (0.5%). Caution is advised in use of Savella in patients with a history of dysuria, notably in male patients with prostatic hypertrophy, prostatitis, and other lower urinary tract obstructive disorders. Male patients are more prone to genitourinary adverse effects, such as dysuria or urinary retention, and may experience testicular pain or ejaculation disorders. Controlled Narrow-Angle Glaucoma-Mydriasis has been reported in association with SNRIs and Savella; therefore, Savella should be used cautiously in patients with controlled narrow-angle glaucoma. Do not use Savella in patients with Uncontrolled Narrow-Angle Glaucoma [see Contraindications]. Concomitant Use with Alcohol-In clinical trials, more patients treated with Savella developed elevated transaminases than did placebo treated patients [see Warnings and Precautions]. Because it is possible that milnacipran may aggravate pre-existing liver disease, Savella should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease. ADVERSE REACTIONS: Clinical Trial Data Sources-Savella was evaluated in three double-blind placebo-controlled trials involving 2209 fibromyalgia patients (1557 patients treated with Savella and 652 patients treated with placebo) for a treatment period up to 29 weeks. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions Leading to Discontinuation-In placebo-controlled trials in patients with fibromyalgia, 23% of patients treated with Savella 100 mg/day, 26% of patients treated with Savella 200 mg/day discontinued prematurely due to adverse reactions, compared to 12% of patients treated with placebo. The adverse reactions that led to withdrawal in 1% of patients in the Savella treatment group and with an incidence rate greater than that in the placebo treatment group were nausea (milnacipran 6%, placebo 1%), palpitations (milnacipran 3%, placebo 1%), headache (milnacipran 2%, placebo 0%), constipation (milnacipran 1%, placebo 0%), heart rate increased (milnacipran 1%, placebo 0%), hyperhidrosis (milnacipran 1%, placebo 0%), vomiting (milnacipran 1%, placebo 0%), and dizziness (milnacipran 1% and placebo 0.5%). Discontinuation due to adverse reactions was generally more common among patients treated with Savella 200 mg/day compared to Savella 100 mg/day. Most Common Adverse Reactions-In the placebo-controlled fibromyalgia patient trials the most frequently occurring adverse reaction in clinical trials was nausea. The most common adverse reactions (incidence 5% and twice placebo) in patients treated with Savella were constipation, hot flush, hyperhidrosis, vomiting, palpitations, heart rate increased, dry mouth, and hypertension. Table 2 lists all adverse reactions that occurred in at least 2% of patients treated with Savella at either 100 or 200 mg/day and at an incidence greater than that of placebo. Table 2. Treatment-Emergent Adverse Reaction Incidence in Placebo-Controlled Trials in Fibromyalgia Patients (Events Occurring in at Least 2% of All Savella-Treated Patients and Occurring More Frequently in Either Savella Treatment Group Than in the Placebo Treatment Group) System Organ Class Savella Savella All Savella Placebo Preferred Term 100 mg/day 200 mg/day (n = 1557) % (n = 652) % (n = 623) % (n = 934) % Cardiac Disorders Palpitations Tachycardia Eye Disorders Vision blurred Gastrointestinal Disorders Nausea Constipation Vomiting Dry mouth Abdominal pain General Disorders Chest pain Chills Chest discomfort Infections Upper respiratory tract infection Investigations Heart rate increased Blood pressure increased Metabolism and Nutrition Disorders Decreased appetite Nervous System Disorders Headache Dizziness Migraine Paresthesia Tremor Hypoesthesia Tension headache Psychiatric Disorders Insomnia Anxiety Respiratory Disorders Dyspnea Skin Disorders Hyperhidrosis Rash Pruritus

17 Red Rock Casino, Resort, and Spa Las Vegas, NV news 17 RECAP Sometimes, Laughter Really Is the Best Medicine What makes something funny? What makes us laugh? Humor can take many forms, said Hob Osterlund, APRN, at the start of her presentation The Role of Humor in Pain Management. By way of illustration, Osterlund, a self-described avid birder, offered several images of albatrosses engaging in what she called their flirting behavior. The albatross and many birds are entertaining, Osterlund said, not because they have a punch line but because they have a comedic presence. The creator of the comedic character Ivy Push (or rather, as Osterlund said, She created me. She just started talking one day and I figured it was time to let her out. ) knows Table 2. Treatment-Emergent Adverse Reaction Incidence in Placebo-Controlled Trials in Fibromyalgia Patients (Events Occurring in at Least 2% of All Savella-Treated Patients and Occurring More Frequently in Either Savella Treatment Group Than in the Placebo Treatment Group)(continued) System Organ Class Savella Savella All Savella Placebo Preferred Term 100 mg/day 200 mg/day (n = 1557) % (n = 652) % (n = 623) % (n = 934) % Vascular Disorders Hot flush Hypertension Flushing Weight Changes-In placebo-controlled fibromyalgia clinical trials, patients treated with Savella for up to 3 months experienced a mean weight loss of approximately 0.8 kg in both the Savella 100 mg/day and the Savella 200 mg/day treatment groups, compared with a mean weight loss of approximately 0.2 kg in placebo-treated patients. Genitourinary Adverse Reactions in Males-In the placebo-controlled fibromyalgia studies, the following treatment-emergent adverse reactions related to the genitourinary system were observed in at least 2% of male patients treated with Savella, and occurred at a rate greater than in placebo-treated male patients: dysuria, ejaculation disorder, erectile dysfunction, ejaculation failure, libido decreased, prostatitis, scrotal pain, testicular pain, testicular swelling, urinary hesitation, urinary retention, urethral pain, and urine flow decreased. Other Adverse Reactions Observed During Clinical Trials of Savella in Fibromyalgia-Following is a list of frequent (those occurring on one or more occasions in at least 1/100 patients) treatment-emergent adverse reactions reported from 1824 fibromyalgia patients treated with Savella for periods up to 68 weeks. The listing does not include those events already listed in Table 2, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life threatening. Adverse reactions are categorized by body system and listed in order of decreasing frequency. Adverse reactions of major clinical importance are described in the Warnings and Precautions section. Gastrointestinal Disorders diarrhea, dyspepsia, gastroesophageal reflux disease, flatulence, abdominal distension; General Disorders fatigue, peripheral edema, irritability, pyrexia; Infections urinary tract infection, cystitis; Injury, Poisoning, and Procedural Complications contusion, fall; Investigations weight decreased or increased; Metabolism and Nutrition Disorders hypercholesterolemia; Nervous System Disorders somnolence, dysgeusia; Psychiatric Disorders depression, stress; Skin Disorders night sweats Postmarketing Spontaneous Reports-The following additional adverse reactions have been identified from spontaneous reports of Savella received worldwide. These adverse reactions have been chosen for inclusion because of a combination of seriousness, frequency of reporting, or potential causal connection to Savella. However, because these adverse reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events include: Blood and Lymphatic System Disorders leukopenia, neutropenia, thrombocytopenia; Cardiac Disorders supraventricular tachycardia; Eye Disorders accommodation disorder; Endocrine Disorders hyperprolactinemia; Hepatobiliary Disorders hepatitis; Metabolism and Nutrition Disorders anorexia, hyponatremia; Musculoskeletal and Connective Tissue Disorders rhabdomyolysis; Nervous System Disorders convulsions (including grand mal), loss of consciousness, Parkinsonism; Psychiatric Disorders delirium, hallucination; Renal and Urinary Disorders acute renal failure, urinary retention; Reproductive System and Breast Disorders galactorrhea; Skin Disorders erythema multiforme, Stevens Johnson syndrome; Vascular Disorders hypertensive crisis DRUG INTERACTIONS: Milnacipran undergoes minimal CYP450 related metabolism, with the majority of the dose excreted unchanged in urine (55%), and has a low binding to plasma proteins (13%). In vitro and in vivo studies showed that Savella is unlikely to be involved in clinically significant pharmacokinetic drug interactions [see Pharmacokinetics in Special Populations]. Clinically Important Interactions with Other Drugs-Lithium: Serotonin syndrome may occur when lithium is co-administered with Savella and with other drugs that impair metabolism of serotonin [see Warnings and Precautions Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-Like Reactions]. Epinephrine and norepinephrine: Savella inhibits the reuptake of norepinephrine. Therefore concomitant use of Savella with epinephrine and norepinephrine may be associated with paroxysmal hypertension and possible arrhythmia [see Warnings and Precautions Effects on Blood Pressure and Effects on Heart Rate] Serotonergic Drugs: Coadministration of Savella with other inhibitors of serotonin re-uptake may result in hypertension and coronary artery vasoconstriction, through additive serotonergic effects [see Warnings and Precautions]. Digoxin: Use of Savella concomitantly with digoxin may be associated with potentiation of adverse hemodynamic effects. Postural hypotension and tachycardia have been reported in combination therapy with intravenously administered digoxin (1 mg). Co-administration of Savella and intravenous digoxin should be avoided [see Warnings and Precautions] Clonidine: Because Savella inhibits norepinephrine reuptake, co-administration with clonidine may inhibit clonidine s anti-hypertensive effect. Clomipramine: In a drug-drug interaction study, an increase in euphoria and postural hypotension was observed in patients who switched from clomipramine to Savella. CNS-active drugs: Given the primary CNS effects of Savella, caution should be used when it is taken in combination with other centrally acting drugs, including those with a similar mechanism of action. Monoamine Oxidase Inhibitors (MAOIs): [see Contraindications]. USE IN SPECIFIC POPULATIONS: Pregnancy-Pregnancy Category C. Milnacipran increased the incidence of dead fetuses in utero in rats at doses of 5 mg/kg/day (0.25 times the MRHD on a mg/m 2 basis). Administration of milnacipran to mice and rabbits during the period of organogenesis did not result in embryotoxicity or teratogenicity at doses up to 125 mg/kg/day in mice (3 times the maximum recommended human dose [MRHD] of 200 mg/day on a mg/m 2 basis) and up to 60 mg/kg/day in rabbits (6 times the MRHD of 200 mg/day on a mg m 2 basis). In rabbits, the incidence of the skeletal variation, extra single rib, was increased following administration of milnacipran at 15 mg/kg/day during the period of organogenesis. There are no adequate and well-controlled studies in pregnant women. Savella should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects; Neonates exposed to dual reuptake inhibitors of serotonin and norepinephrine, or selective T:7.625 in S:7 in a thing or two about the benefits of using humor with patients. In 2005, Osterlund launched the Chuckle Channel, a closed-circuit TV comedy station for hospitals and other healthcare settings that offers uplifting and inclusive funny programming that is suitable for all ages. She and others realized that television is an almost-constant presence for patients in the hospital, and that TVs were often set to 24- hour news channels or even, late at night, to infomercials. That programming can be draining, divisive, and discouraging, said Osterlund. It s important to remember, said Osterlund, that television is not a thing; it s a relationship, even an intimate one. serotonin reuptake inhibitors late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of these classes of drugs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions]. In rats, a decrease in pup body weight and viability on postpartum day 4 were observed when milnacipran, at a dose of 5 mg/kg/day (approximately 0.2 times the MRHD on a mg/m 2 basis), was administered orally to rats during late gestation. The no-effect dose for maternal and offspring toxicity was 2.5 mg/kg/day (approximately 0.1 times the MRHD on a mg/m 2 basis). Labor and Delivery-The effect of milnacipran on labor and delivery is unknown. The use of Savella during labor and delivery is not recommended. Nursing Mothers-There are no adequate and well-controlled studies in nursing mothers. It is not known if milnacipran is excreted in human milk. Studies in animals have shown that milnacipran or its metabolites are excreted in breast milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from milnacipran, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother. Because the safety of Savella in infants is not known, nursing while on Savella is not recommended. Pediatric Use-Safety and effectiveness of Savella in a fibromyalgia pediatric population below the age of 17 have not been established [see Box Warning and Warnings and Precautions]. The use of Savella is not recommended in pediatric patients. Geriatric Use-In controlled clinical studies of Savella, 402 patients were 60 years or older, and no overall differences in safety and efficacy were observed between these patients and younger patients. In view of the predominant excretion of unchanged milnacipran via kidneys and the expected decrease in renal function with age renal function should be considered prior to use of Savella in the elderly [see Dosage and Administration]. SNRIs, SSRIs, and Savella, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions]. DRUG ABUSE AND DEPENDENCE: Controlled Substance - Milnacipran is not a controlled substance. Abuse-Milnacipran did not produce behavioral signs indicative of abuse potential in animal or human studies. Dependence-Milnacipran produces physical dependence, as evidenced by the emergence of withdrawal symptoms following drug discontinuation, similar to other SNRIs and SSRIs. These withdrawal symptoms can be severe. Thus, Savella should be tapered and not abruptly discontinued after extended use [see Discontinuation of Treatment with Savella]. OVERDOSAGE: There is limited clinical experience with Savella overdose in humans. In clinical trials, cases of acute ingestions up to 1000 mg, alone or in combination with other drugs, were reported with none being fatal. In postmarketing experience, fatal outcomes have been reported for acute overdoses primarily involving multiple drugs but also with Savella only. The most common signs and symptoms included increased blood pressure, cardio-respiratory arrest, changes in the level of consciousness (ranging from somnolence to coma), confusional state, dizziness, and increased hepatic enzymes. Management of Overdose-There is no specific antidote to Savella, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug. An adequate airway, oxygenation, and ventilation should be assured and cardiac rhythm and vital signs should be monitored. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Because there is no specific antidote for Savella, symptomatic care and treatment with gastric lavage and activated charcoal should be considered as soon as possible for patients who experience a Savella overdose. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial. In managing overdose, the possibility of multiple drug involvement should be considered. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians Desk Reference (PDR). Manufactured for: Manufactured by: Forest Pharmaceuticals, Inc. Forest Laboratories, Inc. Licensed from Pierre Fabre Medicament and Cypress Bioscience, Inc. Revised: July 2009 People have profound connections to characters on TV. It can help get patients through the night when they are in pain and feeling alone. TV can be a vital means of providing therapeutic presence for patients, especially if the program being watched is humorous. So, back to the question of what is humor and what effect does it have on patients, particularly patients in pain. Quoting Mark Twain, Osterlund said that humor is the goodnatured side of truth. To which she added, Yes, but Humor can be used in many damaging ways as well, she noted. It all depends on how you frame it. Clinicians should be careful to use humor that is not poisonous but is uplifting and therapeutic. In fact, said Osterlund, the Association of Applied and Therapeutic Humor ( defines therapeutic humor as Any intervention that promotes health and wellness by stimulating a playful discovery, expression or appreciation of the absurdity or incongruity of life s situations. This intervention may enhance health or be used as a complementary treatment of illness to facilitate healing or coping, whether physical, emotional, cognitive, social, or spiritual. There have been several studies that have looked at the effect of humor in various patient populations. However, Osterlund noted that there are several shortcomings in many of these trials. They have all been done on healthy adults, most have included only men, none have involved patients who already presented with symptoms, and none have involved oncology patients. Still, several have returned interesting results. One study on laughter s effect on the cardiovascular system asked 20 healthy volunteers to watch two films (one funny, one a war movie). The researchers found consistent vasoconstriction in patients who were watching the war film and consistent vasodilation in patients who were watching the comedy. In a study of humor and fear desensitization, 40 students who were highly afraid of spiders were either exposed to a tarantula or a funny video. The humor and desensitization groups equally and effectively reduced their levels of fear. Another study found that even just the expectation of laughter increased endorphins by 27% and human growth hormone by 87% in 16 healthy males. Other studies have shown that laughter can even increase patients tolerance of pain. Osterlund also shared the results from the Comedy in Chemotherapy Study (COMIC) she conducted, in which outpatient chemotherapy patients watched either a 45-minute comedy film or a 45-minute film of footage of British villages taken from a slow-moving steam train. Patients were assessed pre- and postviewing using the Edmonton Symptom Assessment Scale (ESAS). Investigators also measured patients salivary IgA and cortisol levels before and after they watched the videos. Osterlund reported a greater increase in average IgA and cortisol levels in patients in the humor group. They also showed improvements in the ESAS measures for appetite, sense of well being, pain reduction, and anxiety levels. These results show that television can be an important treatment modality, and clinicians should be thinking about ways in which it might be used therapeutically, said Osterlund. But, she cautioned, it s equally as important that clinicians not force the issue and inject humor where it is not wanted. I would suggest to you that letting patients initiate humor is the right thing. Humor is an intimate thing. The invitation to humor should be sent by the patient. The person who touches first takes the power, just as the person who initiates humor sets the power. Let the patient set the pace.

18 18 news SATURDAY September 12, 2009 Convention&TradeExhibitors 109 Advanced Toxicology Network 316 MEDTOX Laboratories Inc. 203 AIT Laboratories 214 MDNG/Intellisphere, LLC 101 American Society of Pain Educators 106 Ameritox 314 The Apothecary Shops 321 Millennium Laboratories 100 ML International 116 National Fibromyalgia Association Aspen Medical Products 320 Avazzia 118 National Pain Foundation 318 Nevada Psychiatric Association Avee Laboratories, Inc. 303 Outcome Medical, LLC Boston Scientific 309 Calloway Labs 308 Cephalon, Inc. 117 CreoMed Inc. 301 Dannemiller 209 Dominion Diagnostics 103 Eli Lilly & Company 201 Elsevier Medical Publishing 113 Endo Pharmaceuticals 213 GreenValleyMed 111 Healthpac Computer Systems, Inc 315 IDT Supply 121 King Pharmaceuticals, Inc. 307 Las Vegas Recovery Center 211 & 221 Meda Pharmaceuticals 119 Pacific Toxicology Laboratories (Pactox) 317 PainEDU.Org/Inflexxion, Inc 120 Pentec Health Inc. 212 Pharmacy Times 218 PPM Communcations, Inc. 219 Pri-Cara, Division of Ortho-McNeil-Janssen Pharmaceuticals 216 Purdue Pharma, L.P. 305 QuantiaMD 220 Ready for REMS 114 REGISTRAT-MAPI/CPMR Program 104 Sierra Tucson 215 StreamlineMD, LLC 208 Xanodyne Pharmaceuticals Main Entrance red rock Pool Hours 8:00am 7:00pm Unwind with a Massage Make an appointment at the AIT Laboratories booth 203

19 Red Rock Casino, Resort, and Spa Las Vegas, NV news 19 Visiting Las Vegas Beyond the Casinos Visitors to Las Vegas, especially first-timers, can be overwhelmed by the glitz and glitter, the 24/7 activity, and sheer showmanship of the Strip. But beyond the busy casinos, luxury hotels, and fine dining establishments, this town like many other destinations across the country looking for tourism dollars offers a variety of attractions in the hopes of appealing to everyone. Here are some sights not to miss if you prefer an alternative to gaming and shopping. The Stratosphere Tower ( a city landmark, is actually a hotel and casino, but you don t have to be a guest to enjoy the view from this popular observation deck (adult, $15.95). Adventurous types can opt for the X- Scream, a thrill ride that travels 27 feet over the edge of the country s tallest observation deck, or try Insanity, The Ride, a mechanical arm that spins guests 64 feet over the edge, or even ride Big Shot, which plunges guests from the top of the tower. The Big Shot Bar, at the 109th floor near the observation deck, is a more peaceful way to enjoy the spectacular view. Or you can head to the romantic Top of the World restaurant on the 107th floor. Closer to the PAINWeek venue, visitors can experience the state s scenic desert, either by hiking, biking, or driving in the Red Rock Canyon, part of the Red Rock Canyon National Conservation Area ( org) located minutes from the Red Rock Hotel. For only $5, you can take the 13-mile loop by car for spectacular photo opportunities from dawn until dusk in a preserve that spans 197,000 acres of the Mojave Desert. Check out the upgraded exhibit area, 20 hiking trails, and the colorful flora and fauna. In town, wildlife of another sort is on brilliant display at the Bellagio Conservatory & Botanical Gardens (www. Bellagio.com). A massive display of trees, plants and flowers are arranged for each season here by a staff of 140 horticulturalists. Ponds, waterfalls and bridges offer scenic rest areas, 7 days a week, 24 hours a day. AMRIX Rx Only (Cyclobenzaprine Hydrochloride Extended-Release Capsules) Brief Summary of Prescribing Information. The following is a brief summary only. Please see full Prescribing Information for complete product information. DESCRIPTION AMRIX (Cyclobenzaprine Hydrochloride Extended-Release Capsules) is a skeletal muscle relaxant which relieves muscle spasm of local origin without interfering with muscle function. The active ingredient in AMRIX extended-release capsules is cyclobenzaprine hydrochloride, USP. AMRIX extended-release capsules for oral administration are supplied in 15 and 30 mg strengths. INDICATIONS AND USAGE AMRIX is indicated as an adjunct to rest and physical therapy for relief of muscle spasm associated with acute, painful musculoskeletal conditions. Improvement is manifested by relief of muscle spasm and its associated signs and symptoms, namely, pain, tenderness, and limitation of motion. AMRIX should be used only for short periods (up to two or three weeks) because adequate evidence of effectiveness for more prolonged use is not available and because muscle spasm associated with acute, painful musculoskeletal conditions is generally of short duration and specific therapy for longer periods is seldom warranted. AMRIX has not been found effective in the treatment of spasticity associated with cerebral or spinal cord disease or in children with cerebral palsy. CONTRAINDICATIONS Hypersensitivity to any component of this product. Concomitant use of monoamine oxidase (MAO) inhibitors or within 14 days after their discontinuation. Hyperpyretic crisis seizures and deaths have occurred in patients receiving cyclobenzaprine (or structurally similar tricyclic antidepressants) concomitantly with MAO inhibitor drugs. During the acute recovery phase of myocardial infarction, and in patients with arrhythmias, heart block conduction disturbances, or congestive heart failure. Hyperthyroidism. WARNINGS AMRIX is closely related to the tricyclic antidepressants, e.g., amitriptyline and imipramine. In short term studies for indications other than muscle spasm associated with acute musculoskeletal conditions, and usually at doses somewhat greater than those recommended for skeletal muscle spasm, some of the more serious central nervous system reactions noted with the tricyclic antidepressants have occurred (see WARNINGS, below, and ADVERSE REACTIONS section of full Prescribing Information). Tricyclic antidepressants have been reported to produce arrhythmias, sinus tachycardia, prolongation of the conduction time leading to myocardial infarction and stroke. AMRIX may enhance the effects of alcohol, barbiturates, and other CNS depressants. As a result of a two-fold higher cyclobenzaprine plasma levels in subjects with mild hepatic impairment, as compared to healthy subjects, following administration of immediate-release cyclobenzaprine and because there is limited dosing flexibility with AMRIX, use of AMRIX is not recommended in subjects with mild, moderate or severe hepatic impairment. As a result of a 40% increase in cyclobenzaprine plasma levels and a 56% increase in plasma half-life following administration of AMRIX in elderly subjects as compared to young adults, use of AMRIX is not recommended in elderly. PRECAUTIONS General Because of its atropine-like action, AMRIX should be used with caution in patients with a history of urinary retention, angle-closure glaucoma, increased intraocular pressure, and in patients taking anticholinergic medication. Information for Patients AMRIX, especially when used with alcohol or other CNS depressants, may impair mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle. Drug Interactions AMRIX may have life-threatening interactions with MAO inhibitors. (See CONTRAINDICATIONS.) AMRIX may enhance the effects of alcohol, barbiturates, and other CNS depressants. Tricyclic antidepressants may block the antihypertensive action of guanethidine and similarly acting compounds. Tricyclic antidepressants may enhance the seizure risk in patients taking tramadol (ULTRAM [tramadol HCl tablets, Ortho-McNeil Pharmaceutical] or ULTRACET [tramadol HCl and acetaminophen tablets, Ortho-McNeil Pharmaceutical]). Carcinogenesis, Mutagenesis, Impairment of Fertility In rats treated with cyclobenzaprine for up to 67 weeks at doses of approximately 5 to 40 times the maximum recommended human dose, pale, sometimes enlarged, livers were noted and there was a dose-related hepatocyte vacuolation with lipidosis. Cyclobenzaprine did not affect the onset, incidence, or distribution of neoplasia in an 81-week study in the mouse or in a 105-week study in the rat. At oral doses of up to 10 times the human dose, cyclobenzaprine did not adversely affect the reproductive performance or fertility of male or female rats. A battery of mutagenicity tests using bacterial and mammalian systems for point mutations and cytogenic effects have provided no evidence for a mutagenic potential for cyclobenzaprine. Pregnancy Pregnancy Category B: Reproduction studies have been performed in rats, mice, and rabbits at doses up to 20 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to cyclobenzaprine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because cyclobenzaprine is closely related to the tricyclic antidepressants, some of which are known to be excreted in human milk, caution should be exercised when AMRIX is administered to a nursing woman. Pediatric Use Safety and effectiveness of AMRIX has not been studied in pediatric patients. Use in the Elderly The plasma concentration and half-life of cyclobenzaprine are substantially increased in the elderly when compared to the general patient population (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations, Elderly in full Prescribing Information). Accordingly, AMRIX should not be used in the elderly. ADVERSE REACTIONS The most common adverse reactions in the two 14-day clinical efficacy trials are presented in Table 1. Table 1: Incidence of the Most Common Adverse Reactions Occurring in >_ 3% of Subjects in Any Treatment Group in the Two Phase 3, Double-Blind AMRIX Trials In a postmarketing surveillance program (7607 patients treated with cyclobenzaprine 10 mg TID), the adverse reactions reported most frequently were drowsiness, dry mouth, and dizziness. Among the less frequent adverse reactions, there was no appreciable difference in incidence in controlled clinical studies or in the surveillance program. Adverse reactions which were reported in 1% to 3% of the patients were: fatigue/tiredness, asthenia, nausea, constipation, dyspepsia, unpleasant taste, blurred vision, headache, nervousness, and confusion. The following adverse reactions have been reported in post-marketing experience or with an incidence of less than 1% of patients in clinical trials with the 10 mg TID tablet: Body as a Whole: Syncope; malaise. Cardiovascular: Tachycardia; arrhythmia; vasodilatation; palpitation; hypotension. Digestive: Vomiting; anorexia; diarrhea; gastrointestinal pain; gastritis; thirst; flatulence; edema of the tongue; abnormal liver function and rare reports of hepatitis, jaundice, and cholestasis. Hypersensitivity: Anaphylaxis; angioedema; pruritus; facial edema; urticaria; rash. Musculoskeletal: Local weakness. Nervous System and Psychiatric: Seizures, ataxia; vertigo; dysarthria; tremors; hypertonia; convulsions; muscle twitching; disorientation; insomnia; depressed mood; abnormal sensations; anxiety; agitation; psychosis, abnormal thinking and dreaming; hallucinations; excitement; paresthesia; diplopia. Skin: Sweating. Special Senses: Ageusia; tinnitus. Urogenital: Urinary frequency and/or retention. DRUG ABUSE AND DEPENDENCE Pharmacologic similarities among the tricyclic drugs require that certain withdrawal symptoms be considered when AMRIX (Cyclobenzaprine Hydrochloride Extended-Release Capsules) is administered, even though they have not been reported to occur with this drug. Abrupt cessation of treatment after prolonged administration rarely may produce nausea, headache, and malaise. These are not indicative of addiction. OVERDOSAGE Although rare, deaths may occur from overdosage with AMRIX. Multiple drug ingestion (including alcohol) is common in deliberate cyclobenzaprine overdose. As management of overdose is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity may develop rapidly after cyclobenzaprine overdose; therefore, hospital monitoring is required as soon as possible. All patients suspected of an overdose with AMRIX should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage and emesis is contraindicated. The principles of management of child and adult overdosage are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment. DOSAGE AND ADMINISTRATION The recommended adult dose for most patients is one (1) AMRIX 15 mg capsule taken once daily. Some patients may require up to 30 mg/day, given as one (1) AMRIX 30 mg capsule taken once daily or as two (2) AMRIX 15 mg capsules taken once daily. It is recommended that doses be taken at approximately the same time each day. Use of AMRIX for periods longer than two or three weeks is not recommended (see INDICATIONS AND USAGE). Dosage Considerations for Special Patient Populations: AMRIX should not be used in the elderly or in patients with impaired hepatic function (see WARNINGS). HOW SUPPLIED AMRIX extended-release capsules are available in 15 and 30 mg strengths, packaged in bottles of 60 capsules. KEEP THIS AND ALL MEDICATION OUT OF THE REACH OF CHILDREN. IN CASE OF ACCIDENTAL OVERDOSE, SEEK PROFESSIONAL ASSISTANCE OR CONTACT A POISON CONTROL CENTER IMMEDIATELY. Distributed by Cephalon, Inc., Frazer, PA Manufactured by Eurand, Inc., Vandalia, Ohio AMRIX is a trademark of Cephalon, Inc., or its affiliates Cephalon, Inc., or its affiliates. All rights reserved. AMR-2009P-PM Rev. 4/2009

20 AMRIX the shape of once-daily treatment for muscle spasm. Once-daily AMRIX provides early systemic exposure with consistent plasma levels for 24 hours. 1 Single-Day Pharmacokinetic Study: Mean Cyclobenzaprine Concentration Over Time 1 Plasma concentration (ng/ml) = AMRIX 30 mg qd = Cyclobenzaprine IR 10 mg tid Time (hours) qd = once daily; IR = immediate release; tid = 3 times daily Cephalon, Inc. All rights reserved. AMR-2009P-PM Jul 2009 Printed in USA. AMRIX is produced with Eurand Diffucaps technology. AMRIX (Cyclobenzaprine Hydrochloride Extended-Release Capsules) is indicated as an adjunct to rest and physical therapy for relief of muscle spasm associated with acute, painful musculoskeletal conditions. Improvement is manifested by relief of muscle spasm and its associated signs and symptoms; namely, pain, tenderness, and limitation of motion. AMRIX should be used only for short periods (up to 2 or 3 weeks). AMRIX has not been found effective in the treatment of spasticity associated with cerebral or spinal cord disease or in children with cerebral palsy. AMRIX is contraindicated in patients who are hypersensitive to any of its components. AMRIX is contraindicated with concomitant use of monoamine oxidase (MAO) inhibitors or within 14 days after their discontinuation. AMRIX may have life-threatening interactions with MAO inhibitors. AMRIX is contraindicated during the acute recovery phase of myocardial infarction; in patients with arrhythmias, heart block conduction disturbances, or congestive heart failure; or in patients with hyperthyroidism. AMRIX may enhance the effects of alcohol, barbiturates, and other CNS depressants. AMRIX should not be used in elderly patients or in patients with impaired hepatic function. In clinical trials, the most commonly reported adverse reactions ( 3%) with AMRIX were dry mouth, dizziness, fatigue, nausea, dyspepsia, and constipation. Please see brief summary of full prescribing information on the following page. Reference: 1. Data on file. Study Cephalon, Inc.; For more information about AMRIX, visit or call Cephalon at $30 copay coupons available at