The Pain Practitioner - Electric Medicine + Opioid Moral Values

Integrative Pain Management for Optimal Patient Care

The Pain Practitioner SUMMER 2018

Electric Medicine +

Opioid Moral Value, Putting Your Brain to Work, and What Lies Ahead

Academy of Integrative Pain Management

The Pain Practitioner

www.integrativepainmanagement.org

SUMMER 2018

ACADEMY BOARD OF DIRECTORS President W. Clay Jackson, MD, DipTh Past President Joanna Katzman, MD, MSPH Vice President Paul Christo, MD Secretary George D. Comerci, Jr, MD, FACP Treasurer Kevin T. Galloway, BSN, MHA, Colonel, US Army (Retired) Directors-at-Large Lynette Cederquist, MD John Garzione, DPT Michael Kurisu, DO Joseph Matthews, DDS, MSc Roger Mignosa, DO Helen Turner, DNP Liaison to the Board Maggie Buckley

STAFF AND CONSULTANTS

To access the virtual magazine, go to newsstand.aapainmanage.org

9 NOTES FROM THE FIELD On the Moral Value of Pain and Opioids

By Bob Twillman, PhD, FAPM, Executive Director 10 EDITORIAL Is It Still My AIPM?

By W. Clay Jackson, MD, DipTh, Editor-in-Chief PAGE 9

12 ADVOCACY Integrative Pain Care Policy Congress Progress

By Amy Goldstein, MSW, Director of the State Pain Policy Advocacy Network 21 A Treatment Choice

By W. Clay Jackson, MD, DipTh, Editor-in-Chief PAGE 10

Executive Director Robert Twillman, PhD, FAPM Director of the State Pain Policy Advocacy Network (SPPAN) Amy Goldstein, MSW Assistant Director of Education Cathleen Coneghen Director of Legislative and Regulatory Affairs Katie Duensing, JD Member Services Manager Whitney O’Donnell Account Manager Rosemary LeMay Professional Development Project Manager MacKenzie Davis

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THE PAIN PRACTITIONER STAFF AND CONSULTANTS

PAGE 28

Editor-in-Chief W. Clay Jackson, MD, DipTh Editor Debra Nelson-Hogan Managing Editor Cathleen Coneghen Clinical Editor Christine Rhodes, MS Art Director Peter McKinley, Pak Creative Copy Editor Rosemary Hope

11 ANNUAL MEETING/EDUCATION Join Us in Boston in November!

Overview of the Global Pain Clinician Summit 2018: Transforming How We Care for People with Pain.

22 Electric Medicine: Where We Are and Where We Are Headed

By Christine Rhodes, MS 24 Member Profile: Daniel L. Kirsch, PhD

By Debra Nelson-Hogan 28 Putting Your Brain to Work on Your Pain

By Robert Rosen, MD, FAAO, MBA

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The opinions stated in the enclosed printed materials are those of the authors and do not necessarily represent the opinions of the Academy or individual members. The Academy does not give guarantees or any other representation that the printed material contained herein is valid, reliable, or accurate. The Academy of Integrative Pain Management does not assume any responsibility for injury arising from any use or misuse of the printed material contained herein. The printed material contained herein is assumed to be from reliable sources, and there is no implication that they represent the only, or best, methodologies or procedures for the pain condition discussed. It is incumbent upon the reader to verify the accuracy of any diagnosis and drug dosage information contained herein, and to make modifications as new information arises.

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NOTES FROM THE FIELD

On the Moral Value of Pain and Opioids

By Bob Twillman, PhD, FAPM, Executive Director

I’VE BEEN THINKING A LOT ABOUT moral issues related to pain and opioids recently, prompted by some experiences in which I felt as though the person to whom I was listening was absolutely convinced that opioids are always, in every context, evil things. I certainly don’t agree, and hearing this discussion caused me to remember a talk I once heard, and to think a little about the morality of what we do.

Many years ago (I can’t remember exactly, but I do remember a reference to the fact that celecoxib was just about to come onto the market in the United States, an event that happened in 1998), I was honored to witness a presentation by Dr. Dan Brookoff, a hematologist/oncologistturned-pain-physician from Memphis. At the time, I was working at the University of Kansas Hospital, and we scheduled a remarkable series of speakers on topics related to pain management. Those of you who knew Dan undoubtedly will remember a few things about him, including: 1) he was one of the funniest and most entertaining speakers you have ever heard; 2) he was a spiritual man, and generally managed to weave that spirituality into his talks; and 3) he loved to talk about Elvis. As an aside, we got Dan to agree to give a talk provided that he could end it by discussing Elvis’s death and the series of medical misadventures, including treatment of chronic pain, that he believed led up to it.

During the talk, Dan asked the question, “Is pain good or evil?” I’m sure that most people would immediately react by saying that it is evil, and I’m equally sure that that was my first response.

Dan taught the audience that pain is, inherently, neither good nor evil, that the

context of the pain is what determines its moral value. A toddler putting her hand onto a hot stove experiences pain, and that pain causes her to withdraw her hand—that represents a case in which pain is good, because it serves to preserve life and function. Contrast that with a person with chronic arthritis pain, for whom the pain limits function and seeds depression severe enough to prompt thoughts of suicide—that represents a case in which pain is evil, because it limits the life we are meant to lead. Dan’s point was that an experience, such as pain, is morally neutral until we look at its ultimate impact on the person experiencing it.

I believe the same can be said for opioids. As an object, an opioid tablet has no inherent moral value. Used inappropriately, as the object of behavior driven by an opioid use disorder, that tablet can have dire consequences, up to and including the person’s death from an overdose—it is “life-destroying.” Used appropriately, by someone with pain that is not relieved by other means, an opioid can be positively “life-giving.” As with pain, it is the result of using the opioid that determines its moral value.

Which brings me back to the person who started my thought process about the morality of opioids. I occasionally encounter people like this, who are so biased against opioids, for any number of reasons, that they can’t wrap their minds around the possibility that using them can be morally good for some people. For these people, the only good use of an opioid is no use at all.

In their minds, every person should be able to manage his or her pain with

the appropriate non-pharmacological treatments, possibly with the addition of natural or homeopathic medicines, and the inability to do so represents a moral failure on the part of someone, be it the person with pain or the person treating the pain. I think that is a dangerously naïve position that can lead to a cascade of bad outcomes resulting from inappropriate restriction of opioid use.

For what it’s worth, I think there are some people who would argue just as vociferously that NSAIDs are as evil as opioids, if not worse. Many who hold that opinion do so because of a journal article that is a full decade older than Dr. Brookoff’s talk, one that is so shot full of methodological holes that it just doesn’t hold water. But, again, the human tendency to first dichotomize issues and then to label one pole as “bad” and the other as ”good” takes over, and we wind up with people blowing up my Twitter feed telling me that NSAIDs kill more people every year than opioids.

In a world full of gray areas, our desire to simplify decision-making by moralizing can be downright dangerous. As evidence accumulates that short-sighted policies arbitrarily limiting doses of opioids can be “bad” because they result in suicide for some people whose doses are inappropriately and involuntarily tapered, our logical and philosophical foibles become more and more apparent. Folks, it’s always about the patient! It’s about what you intend to do when you provide a particular treatment, about whether you have accumulated sufficient knowledge and developed sufficient skills to deliver that treatment safely and effectively, and about the ultimate outcome achieved by the patient. It’s about whether the treatment limits the patient’s life or enhances it. And that, ultimately, is what we need to focus on as professional helpers.n Bob Twillman, PhD, is the executive director for the Academy of Integrative Pain Management. Dr. Twillman is responsible for overseeing federal and state pain policy developments and advocating for those supporting an integrative approach to managing pain.

He also serves as Chair of the Prescription Monitoring Program Advisory Committee for the Kansas Board of Pharmacy.

THE PAIN PRACTITIONER

| VOLUME 28, NUMBER 2 |

9

EDITORIAL

Is It Still My AIPM?

By W. Clay Jackson, MD, DipTh, Editor-in-Chief

OVER THE PAST DECADE, A SEISMIC shift has occurred nationally with respect to the roles that professional associations play in the lives and careers of their members. In a recent review (1), Denise Lee Yohn explains that three factors have shaken up the 20th-century model of what an association is and does: 1. Members have access to information and training online, from multiple sources, that formerly was only available from associations and sponsored meetings 2. Good, old-fashioned budget cuts 3. Millennial professionals are paradoxically more involved with more causes, but feel less loyalty to any one group Here at AIPM, we’ve felt the impact of those factors, as each of you grapple with a rapidly changing health care environment. In addition, clinicians working in the arena of pain management have struggled with reimbursement changes, societal pressures, and regulatory restrictions that have challenged even seasoned practitioners as they attempt to deliver quality care. At this juncture, waiting to discuss urgent needs that your patients have at a large national meeting, or passively receiving information from experts on their schedule, just doesn’t fit into the way you do work/life balance.

I have great news—we’ve heard from you, in unequivocal terms, what you’re looking for in AIPM. You don’t want simply just a button to wear, or a line on your CV, or to regroup with colleagues once a year in a ballroom. You want a nimble, organic community that drives a conversation that changes the culture of how we treat persons with pain.

To that end, we’ve wiped the slate clean and restructured everything we do to meet those goals. We’ve revamped our annual meeting into shorter, more focused summits, allowing you more frequent access to experts and colleagues, with less travel expense to do so. We’ve expanded our certificate offerings and strengthened the value of those certifications by including maintenance of certification education that not only improves your practice, but signifies to payers and patients that you’re among the best-educated and informed practitioners in the field. We’ve invested heavily in

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online platforms for engaging you and your colleagues in discussions that matter. And finally, we’ve doubled down on advocacy, bringing payers, clinicians, regulators, and legislators to the common table to change the way care is delivered for the better.

move from pain to wellness. I’m proud of that legacy, and we are excited about building on it. Tough times? Absolutely.

But we were built to help you navigate tough times successfully, and to help you to leverage your skills to give your

What can you do to help? A thousand things—but here are a few practical steps that would make a real difference: 1. Get engaged in the conversation.

Send an email to a board member or staff member. Go to Twitter and follow @AAPainManage, or follow AIPM on LinkedIn or like us on Facebook.

When we hear from you, your voice is magnified, and we learn how to help you help your patients.

2. Get involved in leadership. We don’t need a committed minority leading the changes that need to occur in the pain space. We need an army of impassioned, informed clinicians stepping up to help AIPM maximize its potential for good. Here’s a promise: you show the capacity for that leadership, and we’ll find a way for you to contribute.

3. Renew your membership and recruit a colleague. Want to increase your influence? Reproduce yourself by sponsoring someone else to join us in the fight for better care for our patients.

There’s never been a better time to be a part of the only community of clinicians that has always advocated for an integrative approach to helping patients

patients the best outcomes no matter the circumstances.

This is not your grandmother’s AIPM. It’s yours. Seize the opportunity to make it what you’d most like it to be—a vibrant community of committed clinicians, providing education, support, and advocacy across the spectrum of persons with pain and those who treat them. Let’s do this together! n

| TH E PAI N P R AC TITIO N E R | S U M M E R 2018

REFERENCE 1. Yohn DL. To stay relevant, professional associations must rebrand. Harvard Bus Rev. 2016; Jan 5. @mydocjackson W. Clay Jackson, AIPM board president, is clinical assistant professor of family medicine and psychiatry at the University of Tennessee College of Medicine in Memphis, Tennessee, where he maintains a private practice in family and palliative medicine. He is also the medical director of Comprehensive Primary Care, and of Methodist Hospice and Palliative Services. Dr. Jackson is the associate fellowship director of palliative medicine at the University of Tennessee College of Medicine.

ANNUAL MEETING/EDUCATION

GLOBAL PAIN

SUMMIT Join CLINICIAN Us in Boston in November!

Transforming How We Care for People with Pain 2018 Overview of the Global Pain Clinician Summit 2018:

Featuring The Program in Pain.

Transforming HowWorld’s We Only CareCertificate for People with

Nutritional Pain Management

GLOBAL PAIN CLINICIAN SUMMIT

JOIN US

How We Care for People with Pain 2018 Transforming

NOVEMBER 9 -10, 2018

Featuring The World’s Only Certificate Program in

Nutritional Pain Management

as we bring together all members of the pain care team in one place for two full days!

Featuring

The World’s Only Certificate Program in Nutritional Pain Management Register before 6/15/18 to receive $20 off registration with code SUMMIT2018

WWW.INTEGRATIVEPAINMANAGEMENT.ORG/EVENT/SUMMIT2018

AIPM’S INAUGURAL GLOBAL PAIN Clinician Summit 2018: Transforming How We Care for People with Pain will take place at the Joseph B. Martin Conference Center at Harvard Medical Center* in Boston, Massachusetts, Transforming How We Care November 9-10, 2018. for People with Pain “We’ve listened to the needs of today’s busy clinicians, and are excited Featuring to announce a new format for our Annual Meetings that is more contemporary and practices, and discuss practice challenges. relevant for everyone involved, attendees Moreover the Summit includes a full day and commercial supporters alike,” said dedicated to the Certificate in Nutritional Bob Twillman, PhD, AIPM’s Executive Pain Management Program (CNPM), which Director. “Our new format means clinicians was sold out at last year’s annual meeting. can spend less time away from patients, The CNPM, chaired by Robert Bonakdar, and more time learning and connecting MD, FACN, and Nancy, Cotter, MD, FACN, with one another.”

CNS (above), includes a discussion of The Global Pain ClinicianTransforming Summit will How We Care where to start the conversation with patients be more focused, smaller in for size, and with Pain People about using diet and supplements to treat shorter in length than previous Annual pain and includes the five components Meetings. The location has changed necessary in a diet for those in pain. This is from a five-star hotel to an academic Featuring the only certificate program in the world on institution. “Choosing Joseph B. Martin nutritional approaches to managing pain.

Conference Center at Harvard Medical All pain care professionals are encourCenter* reinforces our emphasis on aged to attend, and attendees can earn research and evidence for integrative 13.75 CE/CME. It will be accredited for pain management, and our desire for the physicians, nurses, pharmacists, and meeting to be as affordable and easy to psychologists, and a certificate of attenattend as possible,” Twillman said. dance will be available for all attendees.

The agenda for the Summit focuses For more information, go to on the biggest issues facing today’s http://www.integrativepainmanagement. pain clinicians, including opioid misuse, org/event/Summit2018. n barriers to integrative pain management, digital health, medical marijuana and *Academy of Integrative Pain Management global perspectives on integrative is not affiliated with Harvard University, nor is pain management. There will be many Academy of Integrative Pain Management a opportunities throughout the event for pain Harvard University program or activity. clinicians to meet each other, share best

GLOBAL PAIN CLINICIAN SUMMIT

2018

The World’s Only Certificate Program in Nutritional Pain Management

GLOBAL PAIN CLINICIAN SUMMIT

2018

The World’s Only Certificate Program in Nutritional Pain Management

Learning Objectives After completing this activity, participants will be better able to • Discuss the prevalence and rationale for the use of common integrative therapies in pain management.

• Discuss approaches for coordination of integrative therapies in the management of pain.

• Explain the barriers to an integrative model of care.

• Discuss the benefits and risks of using medical marijuana for chronic pain.

• Describe how to use digital health interventions for optimal patient care.

• Outline the extent of the overlap of chronic pain, opioid use disorders, and mental health disorders.

• Describe how simplistic policy solutions focused on one issue can inadvertently exacerbate the other issues.

• Determine practice change steps and factors.

• List the mechanisms by which nutrients and compounds affect pain.

• Discuss ways in which inflammation related to pain states may be assessed.

• Describe the pathophysiology of osteoarthritis and how it may be impacted by diet.

• Illustrate dietary patterns that modulate inflammation.

THE PAIN PRACTITIONER

| VOLUME 28, NUMBER 2 |

11

ADVOCACY

Integrative Pain Care Policy Congress Progress

By Amy Goldstein, MSW, Director of the State Pain Policy Advocacy Network

Addressing Coverage and Constraints This workgroup is concerned with how the lack of coverage for comprehensive, integrative pain care creates barriers to accessing that care. The workgroup will begin with a comprehensive analysis of policy and coverage issues as they apply to pain care. Co-facilitators are Ravi Prasad, PhD, Associate Chief, Stanford University Division of Pain Medicine; and Doug Metz, DC, Executive Vice president and Chief Services Officer, American Specialty Health.

Promoting Comprehensive, Integrative Pain Care

THE INTEGRATIVE PAIN CARE POLICY CONGRESS, facilitated and convened

by AIPM, continues to make exciting progress toward advancing awareness of, and coverage for, comprehensive, integrative pain care.

The growing number of wellintentioned pain management guidelines and policies —both state and federal— has great impact on the health care that is available to those in need of acute and chronic pain management.

The expertise, effort, and resources required to develop effective plans and interventions that address the public health crises of inadequate pain treatment and opioid-related harms are far beyond the capacities of any one organization. Thus, to advance integrative pain care policy in a smarter, more collaborative way, AIPM facilitated the first Integrative Pain Care Policy Congress in 2017.

At that meeting, 75 leaders from more than 50 organizations representing the full scope of licensed and certified health care providers, payers, research, and policy experts, and patients gathered in San Diego (after months of pre-meeting calls, surveys, draft documents, input, and revisions), in part to collaborate upon a consensus definition of comprehensive, integrative pain care that all could support and/or endorse:

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Comprehensive integrative pain management includes biomedical, psychosocial, complementary health, and spiritual care. It is person-centered and focuses on maximizing function and wellness. Care plans are developed through a shared decision-making model that reflects the available evidence regarding optimal clinical practice and the person’s goals and values.

Participants strongly agreed that workgroups comprised of leaders from a diverse set of organizations and stakeholder views would be necessary to move the ball forward.

THREE WORKGROUPS TO ADVANCE COMPREHENSIVE, INTEGRATIVE PAIN CARE Based on outcomes from the inperson meeting in San Diego, the Pain Policy Congress participants voted from a list of possible workgroups.

There was extremely strong interest in three workgroups from a wide variety of stakeholder groups—each new workgroup ranges from about 15-40 members, and we are committed to ensuring that diverse stakeholder views are reflected in the output from each group.

| TH E PAI N P R AC TITIO N E R | S U M M E R 2018

This workgroup is concerned with how to most effectively promote the use of comprehensive, integrative pain care at the clinical level. The workgroup will begin with an analysis of successful models of comprehensive, integrative pain care, looking for common components that will inform future goals related to expanding access to this type of care. Co-facilitators are Steve Stanos, DO, President, American Academy of Pain Medicine; and Kevin Galloway, BSN, MHA, Colonel, US Army (Retired), Board member, Academy of Integrative Pain Management.

Strategic Communication This group is concerned with how to best communicate the efforts of the Integrative Pain Care Policy Congress to health care providers, policymakers, and others. The workgroup will begin with developing best practices for access to, and distribution of, information generated by the Pain Policy Congress, including but not limited to the consensus definition, blog, position statements, and information about the next in-person meeting. Co-facilitators are Cindy Leyland, Director of Program Operations and PAINS Project Manager for Center for Practical Bioethics; and James Specker, Government and Industry Relations Director, American Massage Therapy Association.

We look forward to sharing more related to these workgroups as they progress.

Each workgroup will be presenting their initial findings/projects at the second in-person meeting of the Integrative Pain Care Policy Congress being held in Boston, Massachusetts on November 10, 2018. n

INDICATIONS AND USAGE

Xtampza® ER (oxycodone) is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Limitations of Use • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve Xtampza ER for use in patients for whom alternative treatment options (eg, non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain • Xtampza ER is not indicated as an as-needed (prn) analgesic

When switching from IR to ER oxycodone, choose Xtampza ER

IMPORTANT SAFETY INFORMATION WARNING: ADDICTION, ABUSE, and MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Addiction, Abuse, and Misuse withdrawal syndrome, which may be lifeRisks From Concomitant Use With Xtampza ER exposes patients and other threatening if not recognized and treated, Benzodiazepines or Other CNS Depressants users to the risks of opioid addiction, abuse, and requires management according Concomitant use of opioids with and misuse, which can lead to overdose to protocols developed by neonatology benzodiazepines or other central nervous and death. Assess each patient’s risk prior experts. If opioid use is required for a system (CNS) depressants, including alcohol, to prescribing Xtampza ER and monitor all prolonged period in a pregnant woman, may result in profound sedation, respiratory patients regularly for the development of advise the patient of the risk of neonatal depression, coma, and death. these behaviors or conditions. opioid withdrawal syndrome and ensure • Reserve concomitant prescribing of that appropriate treatment will be available.

Xtampza ER and benzodiazepines or other Life-Threatening Respiratory Depression CNS depressants for use in patients for Cytochrome P450 3A4 Interaction Serious, life-threatening, or fatal respiratory whom alternative treatment options are The concomitant use of Xtampza ER depression may occur with use of Xtampza inadequate. with all cytochrome P450 3A4 inhibitors ER. Monitor for respiratory depression, • Limit dosages and durations to the may result in an increase in oxycodone especially during initiation of Xtampza ER minimum required. plasma concentrations, which could or following a dose increase. increase or prolong adverse drug effects • Follow patients for signs and symptoms Accidental Ingestion and may cause potentially fatal respiratory of respiratory depression and sedation.

Accidental ingestion of even one dose of depression. In addition, discontinuation Xtampza ER, especially by children, can of a concomitantly used cytochrome P450 result in a fatal overdose of oxycodone.

3A4 inducer may result in an increase in Neonatal Opioid Withdrawal Syndrome oxycodone plasma concentration. Monitor Prolonged use of Xtampza ER during patients receiving Xtampza ER and any pregnancy can result in neonatal opioid CYP3A4 inhibitor or inducer.

Please see additional Important Safety Information and brief summary of full Prescribing Information, including Boxed Warning, on accompanying pages.

Xtampza® ER: The power of ER oxycodone in a novel abuse-deterrent formulation Engineered to deliver pain relief and resist manipulation. However, abuse by injection and via the oral and nasal routes is still possible.

Efficacy

Abuse and Misuse Deterrence

Proven pain relief of ER oxycodone

Maintains its PK profile Provides 12hr action even when manipulated1

12-hour duration of action

The only single-agent ER oxycodone with oral, intranasal, and intravenous abuse-deterrent labelling1,2

• Acetaminophen was the only rescue medication allowed during the clinical study1

The only oral opioid with novel DETERx® abuseProvides 12hr action deterrent technology engineered to resist3: • Crushing • Grinding

• Cutting • Chewing

• Dissolving in solutions • Injecting after crushing, melting, or extracting

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS: • Xtampza ER is contraindicated in patients with significant respiratory depression, acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment, known or suspected gastrointestinal obstruction, including paralytic ileus, and hypersensitivity (eg, anaphylaxis) to oxycodone

WARNINGS AND PRECAUTIONS: Addiction, Abuse, and Misuse • Xtampza ER contains oxycodone, a Schedule II controlled substance. As an opioid, Xtampza ER exposes users to the risks of addiction, abuse, and misuse. As extended-release products such as Xtampza ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of oxycodone present References: 1. Xtampza ER [package insert]. Canton, MA: Collegium Pharmaceutical, Inc.; 2017. 2. OxyContin [package insert]. Stamford, CT: Purdue Pharma LP; 2016. 3. US Food and Drug Administration. FDA advisory committee briefing document: Xtampza ER (extended-release oxycodone). https://www.pharmamedtechbi.com/~/media/Supporting%20Documents/The%20 Pink%20Sheet%20DAILY/2015/September/Collegium_oxycodone_AC_company_brfg.pdf. Published September 11, 2015. Accessed January 31, 2018. 4. Gudin J, Levy-Cooperman N, Kopecky EA, et al. Comparing the effect of tampering on the oral pharmacokinetic profiles of two extended-release oxycodone formulations with abuse-deterrent properties. Pain Med. 2015;16(11):2142-2151. doi:10.1111/pme.12834. 5. Brennan MJ, Kopecky EA, Marseilles A, et al. The comparative pharmacokinetics of physical manipulation by crushing of Xtampza® ER compared with OxyContin®. Pain Manag. 2017;7(6):461-472.

Please see additional Important Safety Information and brief summary of full Prescribing Information, including Boxed Warning, on accompanying pages.

In PK studies of intact vs. crushed product taken orally

Even when manipulated, Xtampza® ER (oxycodone) maintained its Xtended-release PK profile— ® OxyContin did not Head-to-head pharmacokinetic data validated in two separate studies.1,4,5

LABEL UPDATE

Mean Plasma Oxycodone Concentration (ng/mL)

80

Xtampza ER extended-release profile maintained whether crushed or intact.4

70 60 50 40 30 20

Reformulated OxyContin showed a rapid release of oxycodone when crushed.4

10 0 0

1

2

3

4

5

6

7

8

9

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Hours Crushed Xtampza ER

Intact Xtampza ER

Crushed oxycodone IR

Crushed OxyContin

Intact OxyContin

In a 2015 randomized, open-label, active-controlled, five-treatment crossover study, Gudin et al compared the PK of crushed oxycodone IR to Xtampza ER (crushed and intact) and reformulated OxyContin (crushed and intact) taken orally in 42 subjects.1,4

The findings above do not indicate that Xtampza ER can entirely prevent abuse via oral and nasal administration; abuse of Xtampza ER by the oral and nasal routes is still possible.

The impact of the oral PK studies on misuse, abuse, and diversion of Xtampza ER has yet to be determined. Additional data, including epidemiological data, when available, may provide further information on the impact of the current formulation of Xtampza ER on the abuse liability of the drug.

Xtampza ER clinically demonstrated to reduce oral abuse potential vs. oxycodone IR (n=52)1 :

LABEL UPDATE • Statistically lower drug liking (mean) score

• Statistically lower take drug again (mean VAS*) score *VAS: Visual Analog Scale.

Abuse of Xtampza ER by injection and by the oral and nasal routes of administration is still possible.

Learn more at ChooseXtampzaER.com

Xtampza ER and DETERx are registered trademarks of Collegium Pharmaceutical, Inc. OxyContin is a registered trademark of Purdue Pharma, LP. © 2018 Collegium Pharmaceutical, Inc. All rights reserved. PP-XT-US-0835 04/18

IMPORTANT SAFETY INFORMATION for Xtampza® ER (oxycodone) continued Life-Threatening Respiratory Depression • Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended.

Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids Neonatal Opioid Withdrawal Syndrome • Prolonged use of Xtampza ER during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be lifethreatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers • Concomitant use of Xtampza ER with a CYP3A4 inhibitor, such as macrolide antibiotics (eg, erythromycin), azole-antifungal agents (eg, ketoconazole), and protease inhibitors (eg, ritonavir), may increase plasma concentrations of oxycodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of Xtampza ER is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Xtampza ER-treated patients may increase oxycodone plasma concentrations and prolong opioid adverse reactions. When using Xtampza ER with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Xtampza ER-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of Xtampza ER until stable drug effects are achieved • Concomitant use of Xtampza ER with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease oxycodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to oxycodone.

When using Xtampza ER with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur Risks From Concomitant Use With Benzodiazepines or Other CNS Depressants • Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Xtampza ER with benzodiazepines or other CNS depressants (eg, non-benzodiazepine sedatives /hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate • Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics

Risk of Life-threatening Respiratory Depression in Patients With Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of Xtampza ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients With Chronic Pulmonary Disease: Xtampza ER-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Xtampza ER. Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.

Monitor such patients closely, particularly when initiating and titrating Xtampza ER and when Xtampza ER is given concomitantly with other drugs that depress respiration.

Alternatively, consider the use of non-opioid analgesics in these patients. Use an alternative analgesic for patients who require a dose of Xtampza ER less than 9 mg.

Adrenal Insufficiency • Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include nonspecific symptoms and signs, including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency.

The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency Severe Hypotension • Xtampza ER may cause severe hypotension, including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (eg, phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dosage of Xtampza ER. In patients with circulatory shock, Xtampza ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Xtampza ER in patients with circulatory shock Risks of Use in Patients With Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness • In patients who may be susceptible to the intracranial effects of CO2 retention (eg, those with evidence of increased intracranial pressure or brain tumors), Xtampza ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Xtampza ER • Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Xtampza ER in patients with impaired consciousness or coma

Risks of Use in Patients With Gastrointestinal Conditions • Xtampza ER is contraindicated in patients with gastrointestinal obstruction, including paralytic ileus • The oxycodone in Xtampza ER may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms Risk of Use in Patients With Seizure Disorders • The oxycodone in Xtampza ER may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures in other clinical settings associated with seizures.

Monitor patients with a history of seizure disorders for worsened seizure control during Xtampza ER therapy Withdrawal • Avoid the use of mixed agonist/antagonist (eg, pentazocine, nalbuphine, and butorphanol) or partial agonist (eg, buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including Xtampza ER. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms • When discontinuing Xtampza ER, gradually taper the dosage. Do not abruptly discontinue Xtampza ER Risks of Driving and Operating Machinery • Xtampza ER may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Xtampza ER and know how they will react to the medication Laboratory Monitoring • Not every urine drug test for “opioids” or “opiates” detects oxycodone reliably, especially those designed for in-office use. Further, many laboratories will report urine drug concentrations below a specified “cut-off” value as “negative.”

Therefore, if urine testing for oxycodone is considered in the clinical management of an individual patient, ensure that the sensitivity and specificity of the assay is appropriate, and consider the limitations of the testing used when interpreting results ADMINISTRATION WITH FOOD: • Instruct patients to always take Xtampza ER capsules with food and with approximately the same amount of food in order to ensure consistent plasma levels are achieved. For patients who have difficulty swallowing, Xtampza ER can also be taken as a sprinkle on soft foods or sprinkled into a cup and administered directly into the mouth, or through a nasogastric or gastric feeding tube ADVERSE REACTIONS: • The most common adverse reactions (>5%) reported by patients in the Phase 3 clinical trial comparing Xtampza ER with placebo were nausea, headache, constipation, somnolence, pruritus, vomiting, and dizziness Please see brief summary of full Prescribing Information for Xtampza ER on accompanying pages.

Xtampza ER and DETERx are registered trademarks of Collegium Pharmaceutical, Inc. OxyContin is a registered trademark of Purdue Pharma, LP. © 2018 Collegium Pharmaceutical, Inc. All rights reserved. PP-XT-US-0835 04/18

XTAMPZA® ER (OXYCODONE) EXTENDED-RELEASE CAPSULES, FOR ORAL USE, CII BRIEF SUMMARY OF PRESCRIBING INFORMATION (For complete details please see Full Prescribing Information and Medication Guide at XtampzaER.com.)

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYTOCHROME P450 3A4 INTERACTION; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Addiction, Abuse, and Misuse XTAMPZA ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing XTAMPZA ER and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.1)].

Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of XTAMPZA ER. Monitor for respiratory depression, especially during initiation of XTAMPZA ER or following a dose increase [see Warnings and Precautions (5.2)].

Accidental Ingestion Accidental ingestion of even one dose of XTAMPZA ER, especially by children, can result in a fatal overdose of oxycodone [see Warnings and Precautions (5.2)].

Neonatal Opioid Withdrawal Syndrome Prolonged use of XTAMPZA ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be lifethreatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.3)].

Cytochrome P450 3A4 Interaction The concomitant use of XTAMPZA ER with all cytochrome P450 3A4 inhibitors may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression.

In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in oxycodone plasma concentration. Monitor patients receiving XTAMPZA ER and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions (5.5), Drug Interactions (7)].

• Reserve concomitant prescribing of XTAMPZA ER and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.

• Limit dosages and durations to the minimum required.

• Follow patients for signs and symptoms of respiratory depression and sedation.

4 CONTRAINDICATIONS XTAMPZA ER is contraindicated in patients with: • Significant respiratory depression [see Warnings and Precautions (5.2)] • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.6)] • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.10)] • Hypersensitivity (e.g., anaphylaxis) to oxycodone.

5

WARNINGS AND PRECAUTIONS

5.1 Addiction, Abuse, and Misuse XTAMPZA ER contains oxycodone, a Schedule II controlled substance. As an opioid, XTAMPZA ER exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)]. As extended-release products such as XTAMPZA ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of oxycodone present [see Drug Abuse and Dependence (9)].

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed XTAMPZA ER. Addiction can occur at recommended dosages and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing XTAMPZA ER, and monitor all patients receiving XTAMPZA ER for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as XTAMPZA ER, but use in such patients necessitates intensive counseling about the risks and proper use of XTAMPZA ER along with intensive monitoring for signs of addiction, abuse, and misuse.

Abuse or misuse of XTAMPZA ER by snorting or by injecting the dissolved product can result in overdose and death [see Overdosage (10)].

Opioids are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing XTAMPZA ER. Strategies to reduce these risks

include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17)]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended.

Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of XTAMPZA ER, the risk is greatest during the initiation of therapy or following a dosage increase. Closely monitor patients for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of XTAMPZA ER. To reduce the risk of respiratory depression, proper dosing and titration of XTAMPZA ER are essential [see Dosage and Administration (2)].

Overestimating the XTAMPZA ER dose when converting patients from another opioid product can result in a fatal overdose with the first dose.

Accidental ingestion of even one dose of XTAMPZA ER, especially by children, can result in respiratory depression and death due to an overdose of oxycodone.

5.3 Neonatal Opioid Withdrawal Syndrome Prolonged use of XTAMPZA ER during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1), Patient Counseling Information (17)].

5.4 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of XTAMPZA ER with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of oxycodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see Warnings and Precautions (5.2)], particularly when an inhibitor is added after a stable dose of XTAMPZA ER is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in XTAMPZA ER-treated patients may increase oxycodone plasma concentrations and prolong opioid adverse reactions. When using XTAMPZA ER with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in XTAMPZA ER-treated patients, monitor patients closely at frequent intervals and consider dosage reduction of XTAMPZA ER until stable drug effects are achieved [see Drug Interactions (7)].

Concomitant use of XTAMPZA ER with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease oxycodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to oxycodone. When using XTAMPZA ER with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, monitor patients closely at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see Drug Interactions (7)].

5.5 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of XTAMPZA ER with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drugrelated mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7)].

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use.

In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when XTAMPZA ER is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7) and Patient Counseling Information (17)].

5.6 Risk of Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of XTAMPZA ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease: XTAMPZA ER-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of XTAMPZA ER [see Warnings and Precautions (5.2)].

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.

Monitor such patients closely, particularly when initiating and titrating XTAMPZA ER and when XTAMPZA ER is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2)].

Alternatively, consider the use of non-opioid analgesics in these patients.

Use an alternative analgesic for patients who require a dose of XTAMPZA ER less than 9 mg.

5.7 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids.

Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers.

Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

5.8 Severe Hypotension XTAMPZA ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7)]. Monitor these patients for signs of hypotension after initiating or titrating the dosage of XTAMPZA ER. In patients with circulatory shock, XTAMPZA ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of XTAMPZA ER in patients with circulatory shock.

5.9 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), XTAMPZA ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure.

Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with XTAMPZA ER. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of XTAMPZA ER in patients with impaired consciousness or coma.

5.10 Risks of Use in Patients with Gastrointestinal Conditions XTAMPZA ER is contraindicated in patients with gastrointestinal obstruction, including paralytic ileus.

The oxycodone in XTAMPZA ER may cause spasm of the sphincter of Oddi. Opioids may cause increases in the serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

5.11 Risk of Use in Patients with Seizure Disorders The oxycodone in XTAMPZA ER may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during XTAMPZA ER therapy.

5.12 Withdrawal Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including XTAMPZA ER. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

When discontinuing XTAMPZA ER, gradually taper the dosage [see Dosage and Administration (2.5)]. Do not abruptly discontinue XTAMPZA ER. 5.13 Risks of Driving and Operating Machinery XTAMPZA ER may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of XTAMPZA ER and know how they will react to the medication.

5.14 Laboratory Monitoring Not every urine drug test for “opioids” or “opiates” detects oxycodone reliably, especially those designed for in-office use. Further, many laboratories will report urine drug concentrations below a specified “cut-off” value as “negative”. Therefore, if urine testing for oxycodone is considered in the clinical management of an individual patient, ensure that the sensitivity and specificity of the assay is appropriate, and consider the limitations of the testing used when interpreting results.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: • Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)] • Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3)] • Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.5)] • Adrenal Insufficiency [see Warnings and Precautions (5.7)] • Severe Hypotension [see Warnings and Precautions (5.8)] • Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.10)] • Seizures [see Warnings and Precautions (5.11)] • Withdrawal [see Warnings and Precautions (5.12)] 6.1 Clinical Trial Experience 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.

The safety of XTAMPZA ER was evaluated in a Phase 3, randomizedwithdrawal, double-blind clinical trial involving 740 patients with moderate-to-severe chronic lower back pain. In the double-blind maintenance phase, 389 patients were randomized and 193 patients were assigned to the XTAMPZA ER treatment group.

The most common AEs (>5%) reported by patients in the Phase 3 clinical trial during the titration phase were: nausea (16.6%), headache (13.9%), constipation (13.0%), somnolence (8.8%), pruritus (7.4%), vomiting (6.4%), and dizziness (5.7%).

The most common adverse reactions (>5%) reported by patients in the Phase 3 clinical trial comparing XTAMPZA ER with placebo are shown in Table 1 below: Table 1:

Common Adverse Reactions (>5%) Titration

Adverse Reaction Nausea Headache Constipation Somnolence Pruritus Vomiting Dizziness

7 DRUG INTERACTIONS Table 2 includes clinically significant drug interactions with XTAMPZA ER. Table 2:

Examples:

Clinically Significant Drug Interactions with XTAMPZA ER

Inhibitors of CYP3A4 and CYP2D6 Clinical Impact:

Intervention:

Examples:

The concomitant use of XTAMPZA ER and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of XTAMPZA ER and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of XTAMPZA ER is achieved [see Warnings and Precautions (5.4)].

After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone.

Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact:

MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].

Intervention:

The use of XTAMPZA ER is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.

Examples:

Clinical Impact:

XTAMPZA ER (n = 740) (%)

XTAMPZA ER (n = 193) (%)

Placebo (n = 196) (%)

16.6 13.9 13.0 8.8 7.4 6.4 5.7

10.9 6.2 5.2 <1 2.6 4.1 1.6

4.6 11.7 0.5 <1 1.5 1.5 0

In the Phase 3 clinical trial, the following adverse reactions were reported in patients treated with XTAMPZA ER with incidences of 1% to 5%: Eye disorders: vision blurred Gastrointestinal disorders: abdominal pain, upper abdominal pain, diarrhea, gastroesophageal reflux disease General disorders and administration site conditions: chills, drug withdrawal syndrome, fatigue, irritability, edema, pyrexia Injury, poisoning and procedural complications: excoriation Metabolism and nutrition disorders: decreased appetite, hyperglycemia Musculoskeletal and connective tissue disorders: arthralgia, back pain, musculoskeletal pain, myalgia Nervous system disorders: migraine, tremor Psychiatric disorders: anxiety, insomnia, withdrawal syndrome Respiratory, thoracic and mediastinal disorders: cough, oropharyngeal pain Skin and subcutaneous tissue disorders: hyperhidrosis, rash Vascular disorders: hot flush, hypertension In the Phase 3 clinical trial, the following treatment-related adverse reactions were reported in patients treated with XTAMPZA ER with incidences of less than 1% of patients.

Investigations: increased gamma-glutamyl transferase, increased heart rate Nervous system disorders: lethargy, memory impairment, poor-quality sleep Psychiatric disorders: abnormal dreams, euphoric mood, restlessness Respiratory, thoracic and mediastinal disorders: dyspnea Skin and subcutaneous tissue disorders: night sweats 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of oxycodone. Because these reactions are 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.

Serotonin syndrome: Cases of serotonin syndrome, a potentially lifethreatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in XTAMPZA ER. Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids [see Clinical Pharmacology (12.2)].

Intervention:

Examples:

If concomitant use is necessary, consider dosage reduction of XTAMPZA ER until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals.

If a CYP3A4 inhibitor is discontinued, consider increasing the XTAMPZA ER dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.

Clinical Impact: Intervention: Examples:

The concomitant use of XTAMPZA ER and CYP3A4 inducers can decrease the plasma concentration of oxycodone [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone [see Warnings and Precautions (5.4)].

After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.

Butorphanol, nalbuphine, pentazocine, buprenorphine

Clinical Impact:

Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Intervention:

Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of XTAMPZA ER and/or the muscle relaxant as necessary.

Clinical Impact:

Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

Intervention:

Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs Clinical Impact:

The concomitant use of anticholinergic drugs may increase risk of urinary retention and/ or severe constipation, which may lead to paralytic ileus.

Intervention:

Monitor patients for signs of urinary retention or reduced gastric motility when XTAMPZA ER is used concomitantly with anticholinergic drugs.

Rifampin, carbamazepine, phenytoin

Due to additive pharmacological effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.

Intervention:

Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.5)].

Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.

Serotonergic Drugs

Intervention:

Avoid concomitant use.

Diuretics

If concomitant use is necessary, consider increasing the XTAMPZA ER dosage until stable drug effects are achieved [see Dosage and Administration (2.4)]. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider XTAMPZA ER dosage reduction and monitor for signs of respiratory depression.

Clinical Impact:

Clinical Impact:

May reduce the analgesic effect of XTAMPZA ER and/or precipitate withdrawal symptoms.

Muscle Relaxants

Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)

Benzodiazepines and other Central Nervous System (CNS) Depressants

Examples:

phenelzine, tranylcypromine, linezolid

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics

CYP3A4 Inducers

Maintenance

Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.

If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment.

Discontinue XTAMPZA ER if serotonin syndrome is suspected.

8

USE IN SPECIFIC POPULATIONS

8.1 Pregnancy Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.3)]. There are no available data with XTAMPZA ER in pregnant women to inform a drug-associated risk for major birth defects and miscarriage.

In animal reproduction studies, there was no embryo-fetal toxicity when oxycodone hydrochloride was orally administered to rats and rabbits, during the period of organogenesis, at doses 1.3 to 40 times the adult human dose of 60 mg/day, respectively. In a pre- and postnatal toxicity study, when oxycodone was orally administered to rats, there was transiently decreased pup body weight during lactation and the early post-weaning period at the dose equivalent to an adult dose of 160 mg/day. In several published studies, treatment of pregnant rats with oxycodone hydrochloride at clinically relevant doses and below resulted in neurobehavioral effects in offspring [see Data]. Based on animal data, advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations Fetal/neonatal adverse reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration of use, and severity of neonatal opioid withdrawal syndrome may vary based on the specific opioid used, duration of use, timing and amount of last maternal use,

and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.3)].

Labor or delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid induced respiratory depression in the neonate. XTAMPZA ER is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including XTAMPZA ER, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions.

However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression

8.7 Renal Impairment In patients with renal impairment, as evidenced by decreased creatinine clearance (<60 mL/min), the concentrations of oxycodone in the plasma are approximately 50% higher than in subjects with normal renal function. Follow a conservative approach to dose initiation and adjust according to the clinical situation. Use of alternative analgesics is recommended for patients who require a dose of XTAMPZA ER less than 9 mg. [see Clinical Pharmacology (12.3)].

Data Animal Data Studies with oral doses of oxycodone hydrochloride in rats up to 8 mg/ kg/day and rabbits up to 125 mg/kg/day, equivalent to 1.3 and 40 times an adult human dose of 160 mg/day, respectively on a mg/m2 basis, did not reveal evidence of harm to the fetus due to oxycodone. In a pre- and postnatal toxicity study, female rats received oxycodone during gestation and lactation. There were no drug-related effects on reproductive performance in these females or any long-term developmental or reproductive effects in pups born to these rats. Decreased body weight was found during lactation and the early post-weaning phase in pups nursed by dams given the highest dose used (6 mg/kg/day, equivalent to an adult human dose of 160 mg/day, on a mg/m2 basis). However, body weight of these pups recovered. In published studies, offspring of pregnant rats administered oxycodone hydrochloride during gestation have been reported to exhibit neurobehavioral effects including altered stress responses and increased anxiety-like behavior (2 mg/kg/day IV from Gestation Day 8 to 21 and Postnatal Day 1, 3, and 5; 0.3-times an adult human oral dose of 60 mg/day on a mg/m2 basis), and altered learning and memory (15 mg/kg/day orally from breeding through parturition; 2.4 times an adult human oral dose of 60 mg/day on a mg/ m2 basis).

9

8.2 Lactation Risk Summary Oxycodone is present in breast milk. Published lactation studies report variable concentrations of oxycodone in breast milk with administration of immediate-release oxycodone to nursing mothers in the early postpartum period. The lactation studies did not assess breastfed infants for potential adverse reactions. Lactation studies have not been conducted with extended-release oxycodone, including XTAMPZA ER, and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with XTAMPZA ER. Clinical Considerations Infants exposed to XTAMPZA ER through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

8.3 Females and Males of Reproductive Potential Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2), Clinical Pharmacology (12.2)].

8.4 Pediatric Use Safety and effectiveness of XTAMPZA ER in pediatric patients below the age of 18 years have not been established.

8.5 Geriatric Use In controlled pharmacokinetic studies in elderly subjects (greater than 65 years) the clearance of oxycodone was slightly reduced. Compared to young adults, the plasma concentrations of oxycodone were increased approximately 15% [see Clinical Pharmacology (12.3)]. Of the total number of subjects entered into the titration phase of the Phase 3 study for XTAMPZA ER (740), 88 (12%) were age 65 and older. In this clinical trial with appropriate initiation of therapy and dose titration, no untoward or unexpected adverse reactions were seen in the elderly patients who received XTAMPZA ER. Thus, the usual doses and dosing intervals may be appropriate for elderly patients. Use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, concomitant disease, and use of other drug therapy.

Respiratory depression is the chief risk in elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were coadministered with other agents that depress respiration. Titrate the dosage of XTAMPZA ER slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.5, 5.6)].

8.6 Hepatic Impairment A study in patients with hepatic impairment demonstrated greater plasma oxycodone concentrations than those seen at equivalent doses in persons with normal hepatic function. A similar effect on plasma oxycodone concentrations can be expected for patients with hepatic impairment taking XTAMPZA ER. Therefore, in the setting of hepatic impairment, start dosing patients at 1/3 to 1/2 the usual starting dose followed by careful dose titration. Use of alternative analgesics is recommended for patients who require a dose of XTAMPZA ER less than 9 mg. [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].

8.8 Sex Differences In pharmacokinetic studies with XTAMPZA ER, healthy female subjects demonstrate up to 20% higher oxycodone plasma exposures than males, even after considering differences in body weight or BMI. The clinical relevance of a difference of this magnitude is low for a drug intended for chronic usage at individualized dosages. In the Phase 3 clinical trial there was a greater frequency of typical opioid adverse events for females than males; there was no male/female difference detected for efficacy.

DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance XTAMPZA ER contains oxycodone, a Schedule II controlled substance.

9.2 Abuse XTAMPZA ER contains oxycodone, a substance with a high potential for abuse similar to other opioids including fentanyl, hydromorphone, methadone, morphine, and oxymorphone. XTAMPZA ER can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1)].

The high drug content in extended-release formulations adds to the risk of adverse outcomes from abuse and misuse.

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.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

“Drug-seeking” behavior is very common to persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers 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 true addiction.

XTAMPZA ER, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful recordkeeping of prescribing information, including quantity, frequency, and renewal requests as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of XTAMPZA ER XTAMPZA ER is for oral use only. Abuse of XTAMPZA ER poses a risk of overdose and death. The risk is increased with concurrent use of XTAMPZA ER with alcohol and other central nervous system depressants.

Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. Abuse Deterrence Studies XTAMPZA ER capsules contain microspheres formulated with inactive ingredients intended to make the formulation more difficult to manipulate for misuse and abuse.

In Vitro Testing In vitro physical and chemical manipulation studies were performed to evaluate the success of different methods of defeating the extendedrelease formulation.

Results support that, relative to immediate-release oxycodone tablets, XTAMPZA ER is less susceptible to the effects of grinding, crushing, and extraction using a variety of tools and solvents.

XTAMPZA ER resisted attempts to pass the melted capsule contents or the microspheres suspended in water through a hypodermic needle.

Pharmacokinetic Studies The pharmacokinetic profile of manipulated XTAMPZA ER capsule contents (36 mg; [equivalent to 40 mg oxycodone HCl]) was characterized following oral (three studies) and intranasal (two studies) administration. The studies were conducted in a randomized, cross-over design. In studies assessing manipulation by crushing, the most effective crushing method identified in previous in vitro studies was applied to the product(s).

Oral Pharmacokinetic Studies, Manipulated and Intact XTAMPZA ER The effect of two types of product manipulation (crushing and chewing) on XTAMPZA ER pharmacokinetics was measured in three studies.

In one oral pharmacokinetic study, XTAMPZA ER capsule contents were crushed or chewed prior to oral administration in healthy, naltrexoneblocked volunteers. The two comparators in this study were intact XTAMPZA ER capsules and an immediate-release solution of oxycodone at an equivalent dose.

In two oral pharmacokinetic studies, XTAMPZA ER capsule contents were crushed prior to oral administration in healthy, naltrexone-blocked volunteers. The comparators in these studies included intact XTAMPZA ER capsules, intact and crushed reformulated OXYCONTIN® (oxycodone hydrochloride) extended-release tablets at an equivalent dose, and crushed immediate-release oxycodone tablets at an equivalent dose.

The data displayed in Table 3 illustrate the findings from the oral pharmacokinetic studies (data were similar for the two oral pharmacokinetic studies comparing XTAMPZA ER to OXYCONTIN).

Collectively, the data demonstrated that crushing or chewing XTAMPZA ER prior to administration did not increase the maximum observed plasma concentration (Cmax) or total exposure (AUC0-INF) relative to dosing the intact product under fed conditions. Relative to immediaterelease oxycodone and crushed reformulated OXYCONTIN (oxycodone hydrochloride) extended-release tablets, the Cmax for all XTAMPZA ER treatments was lower and the Tmax longer, consistent with an extendedrelease profile.

Table 3:

Oxycodone Pharmacokinetic Parameters, Administration of Manipulated and Intact Dosage Forms (36mg of XTAMPZA ER or equivalent) Cmax (ng/mL)

Treatment

Tmax (hr)

AUC0-INF (hr•ng/ mL)

Oral Pharmacokinetic Study 1

Intact XTAMPZA ER Capsules (fed)

62.3 (13.0)

4.0 (1.5-6)

561 (124)

Crushed XTAMPZA ER Capsule Contents (fed)

57.6 (12.6)

4.5 (2.5-6)

553 (134)

Chewed XTAMPZA ER Capsule Contents (fed)

55.6 (10.9)

4.5 (2.5-8)

559 (113)

Immediate-Release Oxycodone Solution (fasted)

115 (27.3)

0.75 (0.5-2)

489 (80.2)

Intact XTAMPZA ER Capsules (fed)

67.5 (17.6)

3.5 (1.25 – 6.0)

581 (138)

Crushed XTAMPZA ER Capsule Contents (fed)

62.9 (12.6)

4.0 (2.0 – 7.0)

597 (149)

Intact reformulated OXYCONTIN (oxycodone hydrochloride) extended-release tablets (fed)

64.9 (13.8)

5.0 (2.010.0)

611 (145)

Crushed reformulated OXYCONTIN (oxycodone hydrochloride) extended-release tablets (fed)

78.4 (12.9)

1.75 (0.55.0)

587 (132)

Crushed ImmediateRelease Oxycodone Tablets (fed)

79.4 (17.1)

1.75 (0.54.0)

561 (146)

Oral Pharmacokinetic Study 2

Values shown for Cmax and AUC0-INF are mean (standard deviation); values shown for Tmax are median (minimum-maximum).

Nasal Pharmacokinetic Studies The pharmacokinetic profile following intranasal administration of crushed XTAMPZA ER capsule contents was characterized in two clinical studies.

In Nasal Pharmacokinetic Study 1, XTAMPZA ER capsule contents (36 mg) were crushed and intranasally administered by non-dependent, naltrexone-blocked subjects with a history of nasal abuse of opioids. The two comparators in this study were intact XTAMPZA ER capsules (oral) and oxycodone HCl powder (intranasal) at an equivalent dose.

In Nasal Pharmacokinetic Study 2, XTAMPZA ER capsule contents (36 mg) were crushed and intranasally administered by non-dependent subjects with a history of nasal abuse of opioids. The two comparators in this study were intact XTAMPZA ER capsules (oral) and crushed oxycodone immediate-release tablets (intranasal) at an equivalent dose.

The results of Nasal Pharmacokinetic Studies 1 and 2 are comparable and both studies demonstrated that intranasal administration of crushed XTAMPZA ER capsule contents did not result in higher peak plasma concentration (Cmax) or shorter time to peak concentration (Tmax) than taking XTAMPZA ER orally. The data from Nasal Pharmacokinetic Study 2 are displayed in Table 4 to represent these findings.

Table 4:

Oxycodone Pharmacokinetic Parameters, Nasal Pharmacokinetic Study 2:

Treatment

Cmax (ng/mL)

Tmax (hr)

AUC0-INF (hr•ng/ mL)

41.0 (10.0)

5.1 (1.68.1)

477 (89.6)

29.8 (6.6)

5.1 (1.612.1)

459 (106)

60.9 (11.9)

2.6 (0.36.1)

577 (124)

Intact XTAMPZA ER Capsules (oral) Crushed XTAMPZA ER Capsule Contents (nasal) Crushed ImmediateRelease Tablets (nasal)

Values shown for Cmax and AUC0-INF are mean (standard deviation); values shown for Tmax are median (minimum-maximum).

Clinical Studies Oral Abuse Potential Studies: The oral abuse potential of chewed XTAMPZA ER was evaluated in two studies.

In a randomized, double-blind, active- and placebo-controlled, singledose, six-way crossover pharmacodynamic study, 52 non-dependent recreational opioid users received orally-administered active and placebo treatment. The six treatment arms were intact XTAMPZA ER (36 mg, fed and fasted); chewed XTAMPZA ER (36 mg, fed and fasted); crushed immediate-release (IR) oxycodone HCl in solution (40 mg, fasted, equivalent to 36 mg of XTAMPZA ER), and placebo. Data for chewed and intact XTAMPZA ER and crushed IR oxycodone in the fasted state are described below.

Drug Liking was measured on a bipolar 100-point Visual Analog Scale (VAS) where 50 represents a neutral response, 0 represents maximum disliking, and 100 represents maximum liking. Response to whether the subject would take the study drug again was also measured on a bipolar 100-point VAS where 50 represents a neutral response, 0 represents the strongest negative response (e.g., ‘definitely would not take drug again’), and 100 represents the strongest positive response (e.g., ‘definitely would take drug again’).

Fifty-two subjects completed the study, and the results are summarized in Table 5. The oral administration of chewed and intact XTAMPZA ER in the fasted state was associated with statistically lower mean Drug Liking and Take Drug Again VAS scores compared with crushed immediaterelease oxycodone. In addition, the Drug Liking and Take Drug Again scores were similar for XTAMPZA ER taken in the intact and chewed states.

Table 5:

Drug Liking* (Emax)

Summary of Maximum Drug Liking and Take Drug Again (Emax) Following Intranasal Administration XTAMPZA ER Intranasal

Crushed IR Oxycodone Intranasal

Placebo

Drug Liking* (Emax)

Mean (SD)

61.81 (15.64)

82.72 (10.95)

54.5 (11.77)

Median (Range)

59.5 (16-94)

84 (60-100)

51 (28-93)

Take Drug Again* (Emax)

Mean (SD)

47.67 (27.84)

71.36 (23.49)

45.92 (17.50)

50 (0-100)

78.5 (18100)

50 (0-97)

Median (Range)

* Bipolar scale (0=maximum negative response, 50=neutral response, 100=maximum positive response).

Emax = maximum (peak) effect; ER = extended-release; IR = immediaterelease; VAS = visual analogue scale; SD=Standard Deviation.

Figure 1 demonstrates a comparison of Drug Liking for intranasal administration of crushed XTAMPZA ER compared to crushed immediaterelease oxycodone in subjects who received both treatments (N=36). The Y-axis represents the percent of subjects attaining a percent reduction in drug liking for XTAMPZA ER vs. immediate-release oxycodone greater than or equal to the value on the X-axis. Approximately 92% (n = 33) of subjects had some reduction in drug liking with XTAMPZA ER relative to crushed immediate-release oxycodone HCl. Approximately 78% (n = 28) of subjects had a reduction of at least 30% in drug liking with XTAMPZA ER compared to crushed immediate-release oxycodone HCl, and approximately 58% (n = 21) of subjects had a reduction of at least 50% in drug liking with XTAMPZA ER compared to crushed immediaterelease oxycodone HCl. Figure 1: Percent Reduction Profiles for Emax of Drug Liking VAS for Crushed XTAMPZA ER vs. Crushed Immediate-release Oxycodone, N=36 Following Intranasal Administration

XTAMPZA ER Intact (Fasted)

XTAMPZA ER Chewed (Fasted)

IR Oxycodone (Fasted)

73.9 (15.10)

73.3 (14.93)

86.40 (12.01)

55.8 (9.94)

73.5 (50100)

73.5 (50-100)

88.5 (52-100)

50.0 (50-86)

Mean (SD)

77.98 (21.07)

77.85 (18.30)

87.69 (12.90)

50.79 (21.41)

Median (Range)

80.5 (1-100)

81.5 (50-100)

90.5 (50-100)

50.0 (0-100)

Mean (SD)

Crushed

A prior, similarly-designed study was also conducted to evaluate the oral abuse potential of chewed XTAMPZA ER. Although the oral administration of chewed and intact XTAMPZA ER in the fasted state was associated with statistically lower mean Drug Liking scores compared with crushed immediate-release oxycodone, the results for Take Drug Again showed small differences that were not statistically significant.

Nasal Abuse Potential Study: In a randomized, double-blind, active- and placebo-controlled, singledose, four-way crossover pharmacodynamic study, 39 recreational opioid users with a history of intranasal drug abuse received nasally administered active and placebo drug treatment. The four treatment arms were crushed XTAMPZA ER 36 mg dosed intranasally; intact XTAMPZA ER 36 mg dosed orally; crushed immediate-release oxycodone HCl 40 mg (equivalent to 36 mg of XTAMPZA ER) dosed intranasally; and placebo. Data for intranasal XTAMPZA ER and crushed immediaterelease oxycodone are described below.

Thirty-six subjects completed the study. Intranasal administration of crushed XTAMPZA ER was associated with statistically lower mean Drug Liking and Take Drug Again scores compared with crushed immediaterelease oxycodone (summarized in Table 6).

10 OVERDOSAGE Clinical Presentation Acute overdosage with XTAMPZA ER can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations [see Clinical Pharmacology (12.2)].

Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.

The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to oxycodone overdose, administer an opioid antagonist. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to oxycodone overdose.

Because the duration of reversal would be expected to be less than the duration of action of oxycodone in XTAMPZA ER, carefully monitor the patient until spontaneous respiration is reliably reestablished. XTAMPZA ER will continue to release oxycodone and add to the oxycodone load for 24 to 48 hours or longer following ingestion necessitating prolonged monitoring. If the response to opioid antagonists is suboptimal or only brief in nature, administer additional antagonist as directed in the product’s prescribing information.

In an individual physically dependent on opioids, administration of the usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

Manufactured by: Patheon Pharmaceuticals, Cincinnati, OH 45237 U.S. Patent Nos. 7,399,488; 7,771,707; 8,449,909; 8,557,291; 8,758,813; 8,840,928; 9,044,398, 9,248,195, 9,592,200; 9,682,075; 9,737,530 and 9,763,883.

Placebo

* Bipolar scale (0=maximum negative response, 50=neutral response, 100=maximum positive response) Emax = maximum (peak) effect; ER = extended-release; IR = immediaterelease; VAS = visual analogue scale; SD=Standard Deviation.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.1)].

Healthcare professionals can telephone Collegium Pharmaceutical’s Medical Affairs Department (1-855-331-5615) for information on this product.

Summary of Maximum Drug Liking and Take Drug Again (Emax) Following Oral Administration

Median (Range) Take Drug Again (Emax)*

Table 6:

Summary The in vitro data demonstrate that XTAMPZA ER has physicochemical properties expected to make abuse by injection difficult. The data from pharmacokinetic and human abuse potential studies, along with support from the in vitro data, also indicate that XTAMPZA ER has physicochemical properties that are expected to reduce abuse via the oral and intranasal routes. The data from the oral pharmacokinetic studies of crushed or chewed XTAMPZA ER demonstrated a lack of dose dumping with no increase in oxycodone levels compared to intact XTAMPZA ER. However, abuse of XTAMPZA ER by injection and by the oral and nasal routes of administration is still possible.

Additional data, including epidemiological data, when available, may provide further information on the impact of the current formulation of XTAMPZA ER on the abuse liability of the drug. Accordingly, this section may be updated in the future as appropriate.

XTAMPZA ER contains oxycodone, an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit, including fentanyl, hydromorphone, methadone, morphine, and oxymorphone. XTAMPZA ER can be abused and is subject to misuse, addiction, and criminal diversion [see Warnings and Precautions (5.1) and Drug Abuse and Dependence (9.1)].

9.3 Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

XTAMPZA ER should not be abruptly discontinued [see Dosage and Administration (2.5)]. If XTAMPZA ER is abruptly discontinued in a physically dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate.

Xtampza ER is a registered trademark of Collegium Pharmaceutical, Inc. OxyContin is a registered trademark of Purdue Pharmaceutical.

This brief summary is based on the Xtampza ER prescribing information.

Revised 11/2017.

COL 005

A Treatment Choice

By W. Clay Jackson, MD, DipTh

The news wasn’t good. The bone scan showed bright spots throughout the image of Kelly’s skeleton, indicating that his prostate cancer had ‘progressed.’ Like many of our medical euphemisms, in this case, ‘progression’ was anything but positive—it meant that Kelly’s life was at risk, and treatment would need to begin immediately if he was to have reasonable chance of extended survival.

His oncologist, a brilliant young clinician, shared the scan findings and their implications in a straightforward but compassionate manner. He then laid out the plans for treatment, including chemotherapy: “It’s not too difficult to take, and shouldn’t make you very sick. Maybe a little bit of tingling and numbness from nerve damage.”

“What will happen to my hands?”

The oncologist stopped writing and looked up. “What do you mean?”

“I’m a chef,” Kelly said. “I have to have feeling in my hands to work.”

The oncologist digested the sudden importance of a fact hidden in the ‘social history’ section of Kelly’s medical record— his profession held deep importance to him, and his approach to treatment would need to take into account any alteration in his ability to function. In short, the chemotherapy-induced peripheral neuropathy that oncology had labeled as a ‘side effect’ was for Kelly a central effect, and it made the proposed course of action a non-starter.

The oncologist turned on his rotating stool, and pivoted in his treatment plan. “I hear you. I think we can treat the cancer a little differently, and still preserve the feeling in your hands.”

Months later, I met Kelly after a referral to our palliative care clinic, which is embedded within the cancer center where he receives treatment. The prostate cancer was active, but it was being held at bay by the regimen he and the oncologist had chosen. Unfortunately, Kelly was suffering intense pain in his bones, due to the metastases that were causing destruction there.

As such, Kelly’s case represents an emerging category of patients who live at the interface that defines an overlap among the fields of oncology, palliative care, and pain management.

Given his metastatic cancer, the moral obligation to provide relief was acute. But his extended prognosis, provided by recent advances in antineoplastic therapy, was highlighting a therapeutic imperative that patient safety and functionality receive strong consideration in formulating his treatment plan.

In a sense, we needed to treat him with the compassion and symptom management urgency of palliative care, but with the focus on improvement of functional capacity and emphasis on safety of chronic pain management.

We tried a number of different medications, from various classes of analgesics. A serotonin-norepinephrine reuptake inhibitor (SNRI) offered some relief, and was efficacious for relieving his depressed mood. A topical anti-inflammatory medication (NSAID) did not help, but an oral NSAID did help a bit. He failed three long-acting opioids in succession, each one because of excessive sedation (even at low doses). Through time, we discovered that Kelly was able to function best on a

regimen of the SNRI, an oral NSAID, and short-acting opioids, given on an as-needed basis. With these medications, he maintained mental clarity, but was able to avoid the worst of the pain, which prevented him from working.

I asked Kelly about his job, and watched his face illuminate immediately. He explained that he works hard to brighten the lives of the residents of a retirement center, not only by preparing delicious food, but by constructing elaborate food and ice sculptures to add beauty and style to each meal.

“When I’m using my hands to help others, I don’t feel the pain,’ he said.

Since that day, Kelly has shared countless pictures of his sculptures with me. Like many of our palliative care patients in the cancer center, he continues to do well, and has an extended prognosis. The cancer isn’t gone, but it has been slowed. The war hasn’t been won, but Kelly lives a dignified and meaningful life on the terms of a negotiated peace.

A patient spoke up for what was important. An oncologist listened, and tailored a treatment not to the protocol, but to the person. A palliative team attended to analgesia, rather than the algorithms. And because of that, in Memphis, watermelons turn into roses, and senior citizens get to luncheon like they’re putting on the Ritz.

Thanks, Kelly. Your hands are helping us all, to learn how postmodern medicine works—lots of tech, yes, but lots of soul as well. n

THE PAIN PRACTITIONER

| VOLUME 28, NUMBER 2 |

21

ELECTRIC MEDICINE: WHERE WE ARE AND WHERE WE ARE HEADED

Electric Medicine: Where We Are and Where We Are Headed

By Christine Rhodes, MS

In first-century ancient Rome, court physician Scribonius Largus reported that a patient relieved his gout pain when he accidently stood on an electrogenic fish. Since then, the use of electrical stimulation has evolved and now includes a variety of devices to eliminate pain. Electrotherapy does not work for everyone. The opinions as well as the data on electrotherapyâ&#x20AC;&#x2122;s effectiveness have been mixed, but in those for whom it does work, pain relief occurs without the burdens of opioid analgesics.

Electrotherapy includes a range of treatments using electricity to reduce pain, improve circulation, repair tissues, strengthen muscles, or promote bone growth, leading to improvements in physical functioning. It is a form of neuromodulation that encompasses noninvasive or minimally invasive techniques such as electro-acupuncture (EA), percutaneous electrical nerve stimulation (PENS), and transcutaneous electrical nerve stimulation (TENS), as well as more invasive spinal cord stimulation (SCS) and peripheral nerve stimulation (PNS).

NONINVASIVE AND MINIMALLY INVASIVE TECHNIQUES Electrotherapy is typically used in conjunction with other treatments, rather than by itself. A noninvasive form of electrotherapy, such as TENS, might be used in conjunction with physical therapy, where it can relieve pain sufficiently for a patient

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to participate more actively in a targeted exercise program. First available in 1974, TENS uses electrodes on sticky pads that are attached via wires to a battery-operated device to deliver low-frequency current across the surface of the skin. The current stimulates the sensory nerves and helps prevent pain signals from reaching the brain. The device also helps increase the bodyâ&#x20AC;&#x2122;s production of its own endorphins and enkephalins.

Conditions responding to TENS include neck pain and stiffness, low back pain, diabetic peripheral neuropathy, and fibromyalgia. A recent meta-analysis found that TENS could significantly reduce pain scores and opioid consumption within the first 48 hours after total knee arthroplasty as well (1).

A stronger, deeper-penetrating method called inferential current therapy (IFC), delivers a higher frequency current along the nerve strands to stimulate the tissues around an injured body part to promote pain relief and healing. IFC is reported to cause less discomfort than other electrical stimulation methods because at higher frequencies the current can pass deeper into the tissues with less resistance (2). IFC is used to treat circulatory disorders, improve range of motion, and reduce edema and muscle spasms.

If TENS therapy has not been successful, PENS may be considered. In PENS, implanted needle electrodes deliver current closer to the nerves or muscles beneath the skin. The treatment is often recommended for diabetic peripheral neuropathy. Another electrotherapy treatment, pulsed electromagnetic field therapy (PEMF), may be useful after spinal fusion surgery to promote bone growth and enhance the strength of the fusion, as well as ease pain. Research has shown its benefits in failed back surgery syndrome (3) and knee pain associated with knee osteoarthritis.

More than a quarter of those with knee pain who had PEMF therapy were able to stop their pain medication (4).

INVASIVE TECHNIQUES For individuals whose back or neck pain has not been relieved by surgery or other treatments, spinal cord stimulation (SCS) may provide the answer. Delivering mild electrical stimulation to nerves along the spinal column, SCS now accounts for 90% of all neuromodulation treatments (5). The spinal cord stimulator is one of the most powerful tools in treating neuropathic pain.

Delivering tiny amounts of electrical energy directly onto the spine, the stimulator interrupts inappropriate pain information being sent to the brain. It also masks the pain in the extremity by creating a tingling sensation. Peripheral nerve field stimulation is a similar technique, but the devices controlling the electrical pulses are placed under the skin in an area near the nerves involved in the pain.

The technique has been used for decades and is being recommended for an increasing number of conditions, including failed back surgery syndrome, cervical and lumbar radiculitis, peripheral neuropathy, and complex regional pain syndrome.

A trial procedure allows the patient to determine whether SCS will be effective before a permanent device is implanted.

Since SCS was first approved in 1989, new features have been developed to make the devices smaller, more effective,

ELECTRIC MEDICINE: WHERE WE ARE AND WHERE WE ARE HEADED

and more comfortable. For example, systems using highfrequency pulses, rather than the low frequencies traditionally used, may be more effective in reducing pain. One study showed that high-frequency therapy reduced pain by more than half in 85% of patients with back pain and 83% of those with leg pain, as compared to 44% of those with back pain and 56% of patients with leg pain using low-frequency therapy. In this study, more patients improved their function and were able to reduce or eliminate opioid use when using high-frequency vs low-frequency therapy (6).

In addition, applying the therapy to the dorsal root ganglion has proven effective in treating groin and foot pain as well as complex regional pain syndrome. A technique called burst SCS, which delivers closely spaced, highfrequency current, has been effective in relieving pain without the associated paresthesia and may be beneficial for patients who have developed tolerance to traditional SCS (7). Other innovations include the availability of devices that are safe to wear during magnetic resonance imaging scans, and miniaturized and wireless systems that minimize surgical implantation incisions and potential complications. Devices that automatically adapt stimulation to patients’ movements or offer multiple stimulation programs, and longer-lasting batteries that can be implanted as long as 25 years before removal are additional advancements.

headache, pain, and Alzheimer’s disease. A noninvasive vagal stimulation device is approved in Europe, but not yet available in the United States. A peripheral nerve stimulator recently approved for chronic pain is tiny enough to be inserted by needle and communicates wirelessly with an external transmitter that delivers electrical pulses.

While neurostimulation can treat chronic pain, the technology may provide other therapies as well. Because nerve signals permeate the entire body, modulating them may work for other medical conditions. For example, neural signaling partially controls inflammation, suggesting that neurostimulation may treat inflammatory disorders such as Crohn’s disease and rheumatoid arthritis.

The therapeutic use of electrical stimulation to influence biological functions or pathological processes has been termed “electroceuticals.” The National Institutes of Health has established the Stimulating Peripheral Activity to Relieve Conditions (SPARC) program to fund the basic exploration of how peripheral nerves’ electrical signals control the function of internal organs. Clinical research is underway to map the nervous system’s role in disease, as well as study the role of electrical stimulation in treating rheumatoid arthritis and chronic conditions including Type 2 diabetes and autoimmune and endocrine disorders.

Christine Rhodes received her MS in Nutrition Science from Columbia University’s Institute of Human Nutrition and is a Certified Holistic Health Coach. She serves as clinical editor of The Pain Practitioner and is a New York City-based medical writer.

WHAT THE FUTURE MAY BRING More recent varieties of electrotherapy include electrical stimulation of the vagus nerve to prevent epileptic seizures and treat severe depression. Research is underway to evaluate vagus nerve stimulation as a treatment for multiple sclerosis,

REFERENCES

CLINICAL RESEARCH IS UNDERWAY TO MAP THE NERVOUS SYSTEM’S ROLE IN DISEASE, AS WELL AS STUDY THE ROLE OF ELECTRICAL STIMULATION IN TREATING RHEUMATOID ARTHRITIS AND CHRONIC CONDITIONS INCLUDING TYPE 2 DIABETES, AUTOIMMUNE, AND ENDOCRINE DISORDERS.

1. Li J, Song Y. Transcutaneous electrical nerve stimulation for postoperative pain control after total knee arthroplasty.

Medicine (Baltimore). 2017;96(3):e8036.

2. Nitchos A. Interferential current therapy. pt Health. January 3, 2017. https://www.pthealth.ca/blog/interferential-currenttherapy/#. Accessed April 26, 2018.

3. Harper WL, Schmidt WK, Kubat NJ, Isenberg RA. An openlabel pilot study of pulsed electromagnetic field therapy in the treatment of failed back surgery syndrome pain. Int Med Case Rep J. 2014;8:13-22.

4. Bagnato GL, Miceli G, Marino N, Sciortino D, Bagnato GF. Pulsed electromagnetic fields in knee osteoarthritis: a double blind, placebo-controlled, randomized clinical trial.

Rheumatology (Oxford). 2016;55(4):755-762.

5. Mehta N. Spinal cord stimulation for chronic back and neck pain. Updated September 23, 2016. Spine-Health. https:// www.spine-health.com/treatment/pain-management/spinalcord-stimulation-chronic-back-and-neck-pain Accessed April 27, 2018.

6. Kapural L, Yu C, Doust MW, et al. Novel 10-kHz Highfrequency Therapy (HF10 Therapy) is superior to Traditional Low-frequency Spinal Cord Stimulation for the Treatment of Chronic Back and Leg Pain: The SENZA-RCT Randomized Controlled Trial. Anesthesiology. 2015;123(4):851-60.

7. Tjepkema-cloostermans MC, De vos CC, Wolters R, Dijkstra-scholten C, Lenders MW. Effect of Burst Stimulation Evaluated in Patients Familiar With Spinal Cord Stimulation.

Neuromodulation. 2016;19(5):492-7.

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MEMBER PROFILE: DANIEL L. KIRSCH, PHD

Member Profile: Daniel L. Kirsch, PhD

By Debra Nelson-Hogan

Dr. Kirsch, his daughters Sasha and Gabrielle, and wife Tracey in Shanghai.

Daniel L. Kirsch, PhD, the inventor of Alpha-Stim® technology, has been a member of AIPM since 1990. At the 2003 American Academy of Pain Management conference, where he was awarded the Richard Weiner Pain Education Award, Dr. Kirsch described himself as a neurobiologist whose studies focus on the field of pain management.

He has spent over 40 years creating, refining, and improving his technology and the protocols to apply it, and in raising awareness and fighting prejudice about Alpha-Stim in order to help people live healthier, happier lives. Over the past 36 years, Alpha-Stim has helped more than 15 million people manage their pain, anxiety, insomnia, and depression. We spoke with him about the creation, growth, and success of Alpha-Stim.

The Pain Practitioner: Since you launched Alpha-Stim, what have been the challenges to get it accepted by clinicians? When you launched it, what was the immediate reaction?

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Dr. Kirsch: I guess I would say the immediate reaction was ridicule. I started Electromedical Products International, Inc. with $25,000 I borrowed at 17% interest. The original Alpha-Stim 2000 was introduced in 1981. It cost $5,850 and weighed 40 pounds. We sold seven that first year. I did not know that FDA regulated devices then.

William Bauer, MD, then chair of otolaryngology at the Cleveland VA and Case Western University, was one of the first clinicians to try it. He was so impressed with the results in Stage IV cancer patients who did not get relief even from high doses of morphine that he published a case series in the AMA’s Archives of Otolaryngology titled “Electrical Treatment of Severe Head and Neck Cancer Pain” (1).

The National Enquirer picked up the Bauer article and made us the cover story. That resulted in 40,000 letters and the single phone line ringing nonstop. I had one employee and no computers, and no business expertise. While we sorted the mail,

MEMBER PROFILE: DANIEL L. KIRSCH, PHD

the FDA came in and closed us down for 110 days. That’s how long it took to get compliant. They didn’t know what they were doing with devices then—they still don’t, really. So we quickly recouped, selling over $1 million worth of Alpha-Stims the first year and coming out with our second product, the Alpha-Stim 350, which is the first homecare microcurrent device. It was about half the size of a shoe box. We advertised a little but mainly encouraged research at universities and promoted the results of the studies. That gave us credibility among a growing number of more holistic, open-minded practitioners. Today we have more research than any other therapeutic device, a huge advertising budget, and our biggest customer is the US military and over 100 VA Medical Centers.

THERE ARE STILL MANY, IF NOT MOST, DOCTORS STUCK IN THE CHEMICAL-ONLY MINDSET. I BELIEVE ALL DOCTORS WANT TO DO GOOD BUT UNFORTUNATELY TOO MANY DEFINE THAT AS ACCEPTANCE

BY THEIR PEERS RATHER THAN RESULTS IN THEIR PATIENTS.

Incidentally, it took until this year for a follow up on [Dr. Bauer’s study] when researchers at the University of Texas MD Anderson [Cancer Center] published a study with phenomenal outcomes on advanced cancer patients (2).”

The Pain Practitioner: Do any disciplines use it more than others?

Dr. Kirsch: Psychiatrists and psychologists use it the most for their anxiety, depression, and insomnia patients.

Rheumatologists and others treating fibromyalgia use it quite a bit, too. There are three American university-based studies and one fMRI study on fibromyalgia. The military, especially Navy SEALS and Special Forces, use it for all the above plus PTSD and pain. The military also uses it in the Army Substance Abuse Program (ASAP). It can wean people off drugs rapidly, usually without withdrawal symptoms.

The government of the United Kingdom is probably about to be our biggest customer as Professor [Richard] Morriss, chief psychiatrist for the National Health Service, recently completed a study (3) on anxiety with great outcomes that also looked at cost effectiveness. It showed better results than psychotherapy and drugs for a fraction of the cost.

Currently if you are diagnosed with anxiety in the UK you get a course of psychotherapy, after a significant wait. If that fails you get the more expensive pharmaceutical regimen. AlphaStim is working its way through the UK government bureaucracy and will soon become the first treatment for anxiety. In fact, they are already using it while people wait for other treatments.

Germany is looking at the British study and may be the next government to embrace it.

The Pain Practitioner: Is Alpha-Stim covered by insurance companies?

Dr. Kirsch: TRICARE is paying for active duty service members, and the VA is handing them out like hotcakes.

Other governments are paying as noted above. Otherwise in the USA if the policy includes durable medical equipment it may reimburse all or part of the cost, but we closed our insurance billing department several years ago because it’s a lot of paperwork for little results. We will, however, help people submit the bill to their own insurance companies.

The Pain Practitioner: How has the technology changed since the launch in 1981?

Dr. Kirsch: The current models are much smaller and cheaper and have more features and are wearable. But the waveform is the important part and our patented waveform is the same as the original, except it is 20% stronger [more current]. It is also more precise thanks to the explosive growth of technology over the past four decades. I think that makes it more efficacious.

The Pain Practitioner: What do you find challenging in the pain field today?

Dr. Kirsch: There are still many, if not most, doctors stuck in the chemical-only mindset. I believe all doctors want to do good but unfortunately too many define that as acceptance by their peers rather than results in their patients. They want to do the most acceptable treatment and continue to do that even if their

THE PAIN PRACTITIONER

| VOLUME 28, NUMBER 2 |

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MEMBER PROFILE: DANIEL L. KIRSCH, PHD

patients don’t improve. Just pile on the drugs or injections as long as insurance is paying for it. It’s a bit delusional.

Doctors are not scientists, and many don’t understand when FDA approves a drug it does not mean the drug is highly effective. Even if it helps a patient a little, how does it fare in a risk-to-reward analysis? We need to increase our expectations from treatments. I advise practitioners to look at effect sizes in studies, not P-values, so they have a better idea how much improvement a patient can expect from a given treatment.

When patients get an Alpha-Stim by asking their doctor for a prescription and then return to their doctor exhibiting objective observable results [e.g., off morphine, out of their wheelchair, etc.] as well as praising our technology, the doctor usually says good for you and never enquires further about getting one to try in their practice for their other patients. It’s bizarre to me.

Personally I love military doctors because they wear the same uniform as their patients and will do everything they can to help. Of course, I’m stereotyping; there are bad military doctors and good civilian doctors but we sell two Alpha-Stims to governments for every one we sell to civilians.

The Pain Practitioner: What are the plans for creating new products? Changing Alpha-Stim?

Dr. Kirsch: My co-patentee, Raymond Chan, and I are currently designing the next set of products which I hope to have ready for distribution by 2020, although that may be optimistic. It will be more computer based and connected to an app that will record the treatment parameters and the patients results in all four indications [pain, anxiety, depression, and insomnia] plus two write-in categories. The app is being tested now on 500 first responders [police and firefighters] and teachers. Teachers have a stressful job and a study in the UK showed it not only helped relax them but not surprisingly it made them better teachers too.

The next generation will also be connectable to monitoring devices, such as biofeedback and neurofeedback. Most importantly, they will be my final contribution, after which I can retire.

somewhat, even for toenail pain. In fact everyone should do CES because life is stressful. That’s why they didn’t ask for volunteers. If it were used more preventatively, I am certain it would slash the suicide rate.

The Pain Practitioner: Is it used in conjunction with other therapies? Behavior modification?

Dr. Kirsch: In America I think it may be illegal not to medicate patients. We never recommend taking away medications until

Thank you

to our Corporate Council Members!

The Pain Practitioner: Are there any pain conditions that lend themselves to cranial electrotherapy stimulation (CES)?

Dr. Kirsch: Absolutely. All central sensitivity syndromes, such as fibromyalgia, chronic pelvic pain, headache and migraine, idiopathic back pain, multiple chemical sensitivity, myofascial pain syndrome, primary dysmenorrhea, phantom pain syndrome, and restless legs syndrome to name a few.

Temporomandibular Joint Disorder (TMD) and migraines respond better to the probe treatments than cranial electrotherapy stimulation (CES) alone. Our best fMRI mechanistic study on Alpha-Stim CES to date was done in China and at Columbia University in New York on Tourette’s Syndrome (4).

But there is another way to look at the benefits for pain patients. I recommend all peripheral treatments be immediately followed by CES. This is because just about everyone with significant pain has a mood [anxiety and depression] problem to some extent, and the brain controls the nervous system. So if you ask me what you should use if you can only do one—peripheral or central [brain] treatment—I will say use CES for everyone. It will help

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Academy of Integrative Pain Management CORPORATE COUNCIL MEMBERSHIP

Contact sales@integrativepain.org or 209-533-9744.

MEMBER PROFILE: DANIEL L. KIRSCH, PHD

the Alpha-Stim proves helpful in each patient. That is true for our research as well. In fact, as long as the medication is stable it is held constant in our studies as long as the subject meets the inclusion criteria. So when you look at the results of our research, you are looking at effects over and above the medication effects.

All our on-label research is available in graphic, summary, and full text form at alpha-stim.com. But it is not only true for medications. Mental health practitioners often use it during talk sessions such as CBT. The biofeedback and neurofeedback communities have embraced it. Occupational therapists use it in conjunction with what they do. Only physical therapists have shunned it, with few exceptions. I think that may be because of our focus on the brain.

The Pain Practitioner: What is the future of CES and of Alpha-Stim?

Dr. Kirsch: It seems to have taken forever, but I believe the Alpha-Stim is finally being accepted as the first-line of treatment by a growing number of professionals, institutions, and governments. It is a disruptive technology, like what the internet did to the post office and computers did to typewriters. Although we have two factories, one in China and one in Texas, where we make the devices for the government, we can hardly keep up with demand. Even the FDA is finally coming around to reclassify CES into Class II where it belongs and, which we have been fighting them on since 1990. In

the near future physics will replace chemistry as the master science for therapeutic health care, just as it has for diagnostic medicine and every other aspect of our lives.

The Pain Practitioner: Over your career, what has been most personally satisfying for you?

Dr. Kirsch: That’s a great question. It is to see, hear, and read about people recovering from long-standing disorders and enjoying a much better quality of life. When Alpha-Stim was new—for about the first 25 years or so—it was usually used as a last resort when everything else failed. Still, the results were robust. I have never been motivated by money, although I have plenty now, there were times I had to work another job to keep the company afloat. Now I have a lake house, a jet boat, and several kayaks to keep me afloat.

But nothing compares to the testimonials we get, and the results I have seen in my 10 years of part-time practice [partnering with physicians].

Also, on a personal note, I am very happy to see my work featured in the 2017 documentary, “Body Electric” (available for purchase at stress.org). I have been on TV news and talk shows a lot, and had hundreds of radio interviews, but I love this movie and it has come at the perfect time as I wind up my career. I am semi-retired but am ready now to drop the semi.

I’ve accomplished enough for one lifetime and have traveled extensively. I just want to slow down and be with my wife and daughters now. n

Where Change Begins®

REFERENCES 1. Bauer W. Electrical treatment of severe head and neck cancer pain. Arch Otolaryngol.

1983;109(6)382-383.

2. Yennurajalingam S, Kang DH, Hwu WJ, et al. Cranial electrotherapy stimulation for the management of depression, anxiety, sleep disturbance, and pain in patients with advanced cancer: a preliminary study. J Pain Symptom Manage. 2018;55(2):198-206.

3. Clinical and cost effectiveness of Alpha-Stim AID Cranial Electrotherapy Stimulations (CES); a naturalistic study in patients with a primary working diagnosis of moderate-to-severe generalised anxiety disorder who did not improve with low intensity psychological therapy intervention.

NHS Health Research Authority research study.

4. Qiao J, Weng S, Wang P, Long J, Wang Z. Normalization of intrinsic neural circuits governing Tourette’s syndrome using electrotherapy stimulation. Trans Biomed Eng. 2015;62(5):1272-1280.

THE PAIN PRACTITIONER

| VOLUME 28, NUMBER 2 |

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PUTTING YOUR BRAIN TO WORK ON YOUR PAIN

Putting Your Brain to Work on Your Pain

By Robert Rosen, MD, FAAO, MBA

THERE CONTINUES TO BE A RISING OPIOID PROBLEM IN the US without a clear solution in sight. The Centers for Disease Control and Prevention (CDC) has reported emergency department visits for opioid overdoses rose 30% in all parts of the US from July 2016 through September 2017(1). People who overdose are more likely to overdose again.

There is a much better, safer alternative for pain management.

Micro current neurofeedback (MCN) is a safe, proven alternative for pain management that can have a significant impact by helping people get control of their lives again (2).

The concept behind IASIS Technologies MCN is to allow the brain to rebalance and optimize itself, which allows the body to properly heal. This is accomplished by applying low-intensity pulses using transcranial electrical stimulation (LIP-tES) with electroencephalography (EEG) monitoring delivered through three small sensors/leads placed at up to 19 specific locations on the head and neck that correlate to specific symptoms. There is a ground lead, an active lead, and a reference lead. These sensors/leads perform two functions. The first is to detect and monitor brainwaves sending the resulting electronic signals to a computer and a specialized EEG processor.

The second function is to deliver feedback to the brain via a 3 Pico watt micro current signal, which is a fraction of a cell phone signal. This low power feedback frequency correlates with the dominant brainwave frequency and the resulting brainwaves are reflected in the EEG monitor. The MCN system uses the EEG input to determine the treatment frequency. If there is normal beta brainwave there is no responding pulse. If beta brainwaves are abnormal, the pulse is sent to the brain 1 Hz higher than the corresponding brainwave to guide it back down to the normal range. The desired outcome is a balanced brainwave state to allow the brain and nervous system to regulate itself.

Allowing the brain to reorganize itself and shift from its formerly fixed patterns, MCN is like rebooting a computer. The body responds by developing new neural pathways, increasing neuroplasticity. It literally allows the brain and nervous system’s chemical imbalances to self-regulate. The nervous system recalibrates and stabilizes, giving the individual the ability to be more resilient, responsive, and grounded. MCN has been utilized effectively for numerous applications, including, but not limited to: • Fatigue and pain conditions, including fibromyalgia, chronic fatigue, chronic pain, neuroinflammatory states (e.g., microglial activation), electromotive force (EMF) sensitivities, and oppositional defiant disorders.

• Addictions, including those to alcohol, prescription medications, nicotine/cigarettes, and recreational substances (cocaine, marijuana, etc.).

• Anxiety, including symptoms of panic attacks, generalized anxiety, impulse control, irritability, emotional outbursts, or wide emotional fluctuations.

• Post traumatic stress disorder (PTSD) symptoms, including hypervigilance, restlessness, and sleeping problems.

• Depression, including bipolar conditions, flat emotions, social withdrawal, feelings of helplessness, deep sadness, loss of energy, lack of motivation, and loss of sense of humor.

• Head trauma, including those with mild/moderate traumatic

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LET NOTHING STOP THEM.™

®

alpha-stim

for anxiety for insomnia for Depression

for Pain

Everyone Has Patients Who Don’t Want or Can’t Tolerate Opioids Opioids are sometimes necessary. However, when a patient refuses to take them, has a history of addiction, or you’re out of medication options, Alpha-Stim provides another tool for your armamentarium. It is fast, safe, and proven effective, even in the most difficult patients, as evidenced by the recent study of advanced cancer patients at The University of Texas MD Anderson Cancer Center.

The brain functions electrochemically and can be readily modified by electrical intervention. Alpha-Stim utilizes Cranial Electrotherapy Stimulation (CES) and Microcurrent Electrical Therapy (MET) to deliver the only patented waveform for a device of its class, with more than 100 clinical studies over 37 years, no serious adverse effects, and no risk of addiction.

LATEST RESEARCH: The university of Texas MD anderson Cancer Center, “Cranial Electrotherapy stimulation for the Management of Depression, anxiety, sleep Disturbance, and Pain in Patients with advanced Cancer”

3.5

2.91

3

2.8

2.77

2.65

2.5 2

9

8.81

Hospital Anxiety and Depression Scale p<0.001

8.5 8 7.5 7

6.89

6.5

6.42

6.24

6.16

6 5.5

Baseline Week 1

Week 2 Week 3

Week 4

5

Baseline Week 1

Week 2

Week 3

Week 4

Pi sburgh Sleep Quality Index p=0.055

11

Mean Insomnia Scores

Brief Pain Inventory p=0.013

3.74

Mean Anxiety Scores

Mean Pain Scores

4

INCREASED SLEEP TIME

DECREASED ANXIETY 9.5

10.5

10.23

10 9.5

8.7

9 8.5

8.4

8 7.5 7

Baseline

Week 2

Week 4

DECREASED DEPRESSION 6.5

Mean Depression Scores

PAIN REDUCTION

6 5.5

6.36

Hospital Anxiety and Depression Scale p=0.024

5.67 5.27

5

5.34 4.97

4.5 4

Baseline Week 1 Week 2

Week 3

Week 4

REFERENCE Yennurajalingam S, Kang D-H, Hwu W-J, Padhye NS, Masino C, Dibaj SS, Liu DD, Williams JL, Lu Z, Bruera E. Cranial electrotherapy stimulation for the management of depression, anxiety, sleep disturbance, and pain in patients with advanced cancer: a preliminary study. Journal of Pain and Symptom Management. 2018 Feb; 55(2): 198-204.

HElP fOr yOur PaTiEnTs is HErE.

To get started and to see more clinical data, visit www.alpha-stim.com/PP or call 1-800-fOr-Pain (in USA) or +940-328-0788 (Outside USA).

Alpha-Stim and the Alpha-Stim logo are registered trademarks, and LET NOTHING STOP THEM is a trademark of Electromedical Products International, Inc. © 2018 Electromedical Products International, Inc. All rights reserved. Read a full disclosure of the minor and self-limiting risks here: alpha-stim.com/risk.

PUTTING YOUR BRAIN TO WORK ON YOUR PAIN

brain injury (TBI), concussions, chronic traumatic encephalopathy (CTE), blast injuries, strokes, cranial surgeries, and seizures.

• Cognitive dysfunction, including ADD/ADHD, some learning disabilities, brain fog, cognitive deficits from stroke, and poor memory.

• Obsessiveness, including compulsions, OCD, Tourette’s syndrome, and some aspects of autistic spectrum disorders.

All the conditions mentioned above have a common denominator: the brain is “frozen” or “stuck” in a dysfunctional pattern. Unlike other neurofeedback, MCN does not attempt to train or shock the brain by using set frequencies or higher current. Instead MCN balances the brain allowing it to reorganize itself and release from frozen, stuck patterns.

This is why medications are often unable to satisfactorily address the above conditions. Medications generally address specific symptoms and will not help the brain achieve its natural state of flexibility, self-regulation, and focus.

He was deployed overseas 10 times with seven combat operations in the Middle East.

During his close encounter combat experience, Greg suffered two major concussive injuries. The first occurred when an armored Humvee he was riding in ran over an improvised explosive device (IED) lifting the vehicle in the air and flipping it over backwards, throwing Greg first into the roof of the vehicle then impacting the ground causing fractured vertebrae and

IT IS ESTIMATED THAT 40%-60% OF ADDICTION IS TIED TO GENETICS.

TRAUMATIC BRAIN INJURY CASE STUDY The success of MCN on trauma and PTSD attracted the attention of the military. This was accomplished by a pilot study funded by IASIS, of “Patient Zero” whom we will refer to as Greg. Greg is a Marine Master Gunnery Sergeant, with a distinguished 30-year career in the Marine Corps, scoring 120 on both the General Technical and General Electrical testing, putting him in the top 1% of military entrants. The majority of Greg’s career was spent with the Marine Corp’s most elite teams, Recon/Force Recon and Special Operations Forces.

broken bones in his left foot, ruptured eardrums in addition to giving him a concussion. This produced weeks of persistent headaches and ringing ears. The second episode occurred when he was struck by shrapnel from a hand grenade that detonated very close to his covered position. The blast caused his helmet to be blown off his head, again causing ringing in his ears for days following the explosion.

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Copyright © 2018 Pearson Education. All rights reserved. Pearson is a trademark, in the U.S. and/or other countries, of Pearson Education, Inc. or its affiliates.

The following are registered trademarks of the Regents of the University of Minnesota: MMPI, MMPI-2-RF, MMPI-A-RF, Minnesota Multiphasic Personality Inventory, and Minnesota Multiphasic Personality Inventory-2-Restructured Form. The following are unregistered, common law trademarks of the University of Minnesota: MMPI-A, Minnesota Multiphasic Personality Inventory-Adolescent, Minnesota Multiphasic Personality Inventory-Adolescent-Restructured Form, MMPI-2, Minnesota Multiphasic Personality Inventory-2, and The Minnesota Report. CLINA15777-11189 ML 4/18

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• Spine Surgery Candidate Interpretive Report • Spinal Cord Stimulator Candidate Interpretive Report Andrew R. Block, PhD & Yossef S. Ben-Porath, PhD

PUTTING YOUR BRAIN TO WORK ON YOUR PAIN

These two incidents combined with the grueling physical demands and micro trauma of his Elite Marine Corps assignments had left a legacy of pain and lost mental acuity. With three decades of Special Operations Forces and close encounter combat experience, and two Purple Hearts to show for it, Greg returned home with severe migraine headaches and extreme depression from his traumatic brain injuries.

Retiring from the Marines in 2007, Greg began seeing both a psychiatrist and a psychologist at the VA hospital in San Diego.

He was also enrolled in a VA-sponsored brain study that was conducted by University of California at San Diego (UCSD) Medical School. The study determined that Greg had experienced a traumatic brain injury (TBI) and was told that he would most likely never regain the mental capabilities he had once possessed.

In Greg’s opinion both the psychiatrist and psychologist had helped reduce symptoms of PTSD but there was no evidence that the TBI was ever going to get better. As a result of the TBI, his speech, attention span, and other areas were severely impaired and impacted. Additionally, Greg was prescribed one prescription after another. Five years of narcotic and psychotropic drug prescriptions did not resolve Greg’s issues and he continued to struggle with PTSD, migraines, and anger issues.

In 2012 IASIS Technologies, Inc. (IASIS) approached UCSD and asked them to conduct a single subject pilot study for MCN using Greg as “Patient Zero” that IASIS would sponsor.

Greg had a migraine when IASIS administered his first MCN treatment and felt it disappear within the first minute of treatment. Greg’s reaction to MCN was nothing short of incredible. He was able to discontinue his prescription medications after his first treatment and could feel himself regaining his prior acuity and energy. Greg had a total of 10 treatments over a three-week period as part of the pilot study guidelines. MCN had in his own words “given him his life back.”

IASIS used quantitative electroencephalography (qEEG) mapping as a primary diagnostic test of brain function, which measures the electrical patterns present on the surface of the scalp (see Figure 1).

Greg’s qEEG results before treatment clearly showed the results of TBI with very little in the normal brainwave activity range. Within 2 standard deviations from the norm on either side is considered normal brain activity. In Greg’s “before” qEEG mapping you can see the excessive activity of his brain that was depicted in red. The red corresponded to the location where Greg’s migraine was concentrated. Greg’s “after” qEEG six

FIGURE 1: BEFORE AND AFTER EEGs.

The individual brain maps (Hz) use colors to represent the Z scores at the 19 reference points, with the nose on the top.

A Z score is a metric, which represents how similar a score is to the “normal population” as defined by the Neuroguide Database.

Z scores represent Standard Deviations (SD) from the norm and span from -3 to +3. A Z score of 0 represents the norm and is color-coded in these set of maps as the color “grey” and or “white.”

THE PAIN PRACTITIONER

| VOLUME 28, NUMBER 2 |

31

PUTTING YOUR BRAIN TO WORK ON YOUR PAIN

weeks later, had changed dramatically showing balanced brain activity, validating the changes that Greg had experienced.

FURTHER RESEARCH Greg’s results prompted the University of California, San Diego (UCSD) School of Medicine to conduct their own study on veterans with PTSD (3). The results documented, via magnetoencephalography (MEG) neuroimaging, showed significantly improved neural functions in all the participants with mild traumatic brain injuries. At the baseline MEG exam, all participants had abnormal slow-waves. In the follow-up MEG exam, the participants showed significantly reduced abnormal slow-waves with an average reduction of 53.6 ± 24.6% in slow-wave total score.

The participants also showed significant reduction of pain catastrophizing scale (PCS) scores after MCN treatments, with an average reduction of 52.76 ± 26.4% in PCS total score.

The results were reported in the September 29, 2017, issue of ScienceDaily(4). The Veterans Administration in San Diego is now following up this study by conducting a double-blind clinical trial that began October 2017. This clinical trial at UCSD will measure the progress of hundreds of veterans who will receive treatments to care for PTSD symptoms.

PTSD and TBI are everyday concerns for a large number of veterans in the US. The UCSD trial will provide empirical data to support the efficacy of a drug-free alternative. The Veterans Administration reports that roughly 22 veterans die by suicide every day (5). That number exceeds the national average by 28%.

From Greg’s firsthand experience with MCN, he is actively

supporting, recruiting, and seeing to the delivery of MCN to as many veterans as possible. This is what clinical trial designers call a twofer—treating patients in real time while the trial is being run. Because MCN is a totally safe treatment there is no risk of adverse effects.

There are currently a number of integrative and functional medical centers offering MCN treatments in the US seeing similar results across the whole spectrum of symptoms. It is estimated that 40%-60% of addiction is tied to genetics. For this reason, NeuroGen in San Diego is designing a validation study, uniting the EpigeneticsRx genetic methylation panel with MCN to study the impact on gene expression. This study will help provide empirical data further supporting organic solutions to chronic ailments.

The impact of these studies will extend beyond reducing the current opioid addiction epidemic and use of psychotropic drugs. The positive financial impact to the US health system could be significant. Greg alone represents a saving to the VA of over $3,000 per month. n Robert S. Rosen, MD, FAAO, MBA, is the acting medical director of IASIS MCN. Dr. Rosen is a board certified Ophthalmologist. He earned a medical degree from the University of Michigan, and an MBA from Pepperdine University. His extensive clinical and corporate experience includes working as medical director for Pearl Visioncare and he is the founder of Pearl Vision Foundation, which provides vision care services to 9,000,000 people worldwide. To learn more about the study feel free to contact the author Dr. Robert Rosen at rsrosenmbamd@yahoo.com.

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1. Opioid overdoses treated in emergency departments. Centers for Disease Control and Prevention.

CDC website. https://www.cdc.gov/ vitalsigns/opioid-overdoses/index. html March 18, 2018. Accessed: March 28, 2018.

2. IASIS Technologies, Inc. website. https://microcurrentneurofeedback. com/iasis-tech/ 3. Huang MX, Swan AR, Quinto AA, et al. A pilot treatment study for mild traumatic brain injury: Neuroimaging changes detected

by MEG after low-intensity pulse-based transcranial electrical stimulation. Brain Inj. 2017;31 (13-14):1951-1963.

4. Transcranial electrical stimulation shows promise for treating mild traumatic brain injury.

ScienceDaily. September 29, 2017. https://wwwsciencedaily.com/ releases/2017/09/170929093048.htm 5. Veterans statistics: PTSD, depression, TBI, suicide.

September 20, 2015. http://www.veteransandptsd.com/ PTSD-statistics.html

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THE PAIN PRACTITIONER

| VOLUME 28, NUMBER 2 |

33

NUCYNTA® ER (tapentadol) IMPORTANT SAFETY INFORMATION (continued) CONTRAINDICATIONS: NUCYNTA ER is contraindicated in patients with: • Significant respiratory depression • Acute or severe bronchial asthma or hypercarbia in an unmonitored setting or in the absence of resuscitative equipment • Known or suspected gastrointestinal obstruction, including paralytic ileus • Hypersensitivity (e.g. anaphylaxis, angioedema) to tapentadol or to any other ingredients of the product • Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days WARNINGS AND PRECAUTIONS: Addiction, Abuse, and Misuse NUCYNTA ER contains tapentadol, a Schedule II controlled substance. As an opioid, NUCYNTA ER exposes users to the risks of addiction, abuse, and misuse. Because extendedrelease products such as NUCYNTA ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of tapentadol present.

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed NUCYNTA ER. Addiction can occur at recommended doses and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing NUCYNTA ER, and monitor all patients receiving NUCYNTA ER for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression).

The potential for these risks should not, however, prevent the prescribing of NUCYNTA ER for the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as NUCYNTA ER, but use in such patients necessitates intensive counseling about the risks and proper use of NUCYNTA ER along with intensive monitoring for signs of addiction, abuse, and misuse.

Life-threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of NUCYNTA ER, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression especially within the first 24-72 hours of initiating therapy with and following dosage increases of NUCYNTA ER. To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA ER are essential. Overestimating the NUCYNTA ER dosage when converting patients from another opioid product can result in fatal overdose with the first dose.

Accidental ingestion of even one dose of NUCYNTA ER, especially by children, can result in respiratory depression and death due to an overdose of tapentadol.

Neonatal Opioid Withdrawal Syndrome Prolonged use of NUCYNTA ER during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Risk from Concomitant Use with Benzodiazepines or Other CNS Depressants Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on Abuse or misuse of NUCYNTA ER by crushing, chewing, snorting, NUCYNTA ER therapy. The co-ingestion of alcohol with NUCYNTA ER may result in increased plasma tapentadol levels and a or injecting the dissolved product will result in the uncontrolled potentially fatal overdose of tapentadol. delivery of tapentadol and can result in overdose and death.

Profound sedation, respiratory depression, coma, and death Opioids are sought by drug abusers and people with addiction may result from the concomitant use of NUCYNTA ER with disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing NUCYNTA ER. Strategies to benzodiazepines or other CNS depressants (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, reduce these risks include prescribing the drug in the smallest muscle relaxants, general anesthetics, antipsychotics, other appropriate quantity and advising the patient on the proper opioids, alcohol). Because of these risks, reserve concomitant disposal of unused drug. Contact the local state professional prescribing of these drugs for use in patients for whom licensing board or state controlled substances authority for alternative treatment options are inadequate. information on how to prevent and detect abuse or diversion of this product.

NUCYNTAÂŽ ER (tapentadol) IMPORTANT SAFETY INFORMATION (continued) Risk from Concomitant Use with Benzodiazepines or Other CNS Depressants (continued) Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics.

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response.

Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when NUCYNTA ER is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressants have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs.

Risk of Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of NUCYNTA ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease: NUCYNTA ER-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of NUCYNTA ER. Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Alternatively, consider the use of non-opioid analgesics in these patients.

Monitor such patients closely, particularly when initiating and titrating NUCYNTA ER and when NUCYNTA ER is given concomitantly with other drugs that depress respiration.

Serotonin Syndrome with Concomitant Use of Serotonergic Drugs Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of tapentadol with serotonergic drugs. Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). This may occur within the recommended dosage range.

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, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that. Discontinue NUCYNTA ER if serotonin syndrome is suspected.

Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids.

Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Severe Hypotension NUCYNTA ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients.

There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics).

Monitor these patients for signs of hypotension after initiating or titrating the dosage of NUCYNTA ER. In patients with circulatory shock, NUCYNTA ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of NUCYNTA ER in patients with circulatory shock.

NUCYNTA® ER (tapentadol) IMPORTANT SAFETY INFORMATION (continued) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), NUCYNTA ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with NUCYNTA ER. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of NUCYNTA ER in patients with impaired consciousness or coma.

Risks of Use in Patients with Gastrointestinal Conditions NUCYNTA ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The tapentadol in NUCYNTA ER may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Risk of Use in Patients With Seizure Disorders The tapentadol in NUCYNTA ER may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during NUCYNTA ER therapy.

Risks of Driving and Operating Machinery NUCYNTA ER may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of NUCYNTA ER and know how they will react to the medication.

Risk of Toxicity in Patients with Hepatic Impairment A study with an immediate-release formulation of tapentadol in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Avoid use of NUCYNTA ER in patients with severe hepatic impairment. Reduce the dose of NUCYNTA ER in patients with moderate hepatic impairment. Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression when initiating and titrating NUCYNTA ER. Risk of Toxicity in Patients with Renal Impairment Use of NUCYNTA ER in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known.

ADVERSE REACTIONS: In clinical studies, the most common (≥10%) adverse reactions were nausea, constipation, dizziness, headache, and somnolence.

Please see Brief Summary, including BOXED WARNING, on the following pages.

Withdrawal Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including NUCYNTA ER. In these patients, mixed agonists/ antagonists and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

When discontinuing NUCYNTA ER, gradually taper the dose.

Do not abruptly discontinue NUCYNTA ER.

© 2018 Collegium Pharmaceutical, Inc. All rights reserved. PP-NUER-US-0029 02/18

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION This does not include all the information needed to use NUCYNTA ER safely and effectively. See full Prescribing Information for NUCYNTA ER. INDICATIONS AND USAGE NUCYNTA ER (tapentadol) is indicated for the management of: • pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate • neuropathic pain associated with diabetic peripheral neuropathy (DPN) severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Limitations of Usage • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations (see Warnings and Precautions), reserve NUCYNTA ER for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

• NUCYNTA ER is not indicated as an as-needed (prn) analgesic.

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTION WITH ALCOHOL and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS See full prescribing information for complete boxed warning.

• NUCYNTA ER exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor regularly for development of these behaviors or conditions. (5.1) • Serious, life-threatening, or fatal respiratory depression may occur.

Monitor closely, especially upon initiation or following a dose increase.

Instruct patients to swallow NUCYNTA ER tablets whole to avoid exposure to a potentially fatal dose of tapentadol. (5.2) • Accidental ingestion of NUCYNTA ER, especially in children, can result in fatal overdose of tapentadol. (5.2) • Prolonged use of NUCYNTA ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (5.3).

• Instruct patients not to consume alcohol or any products containing alcohol while taking NUCYNTA ER because co-ingestion can result in fatal plasma tapentadol levels. (5.4) • Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. (5.4), (7).

CONTRAINDICATIONS NUCYNTA ER is contraindicated in patients with: • Significant respiratory depression • Acute or severe bronchial asthma or hypercarbia in an unmonitored setting or in the absence of resuscitative equipment • Known or suspected gastrointestinal obstruction, including paralytic ileus • Hypersensitivity (e.g. anaphylaxis, angioedema) to tapentadol or to any other ingredients of the product (see Adverse Reactions).

• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days (see Drug Interactions).

WARNINGS AND PRECAUTIONS Addiction, Abuse, and Misuse NUCYNTA ER contains tapentadol, a Schedule II controlled substance. As an opioid, NUCYNTA ER exposes users to the risks of addiction, abuse, and misuse.

Because extended-release products such as NUCYNTA ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of tapentadol present (see Drug Abuse and Dependence).

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed NUCYNTA ER. Addiction can occur at recommended doses and if the drug is misused or abused.

Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing NUCYNTA ER, and monitor all patients receiving NUCYNTA ER for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression).

The potential for these risks should not, however, prevent the prescribing of NUCYNTA ER for the proper management of pain in any given patient.

Patients at increased risk may be prescribed opioids such as NUCYNTA ER, but use in such patients necessitates intensive counseling about the risks and proper use of NUCYNTA ER along with intensive monitoring for signs of addiction, abuse, and misuse.

Abuse or misuse of NUCYNTA ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of tapentadol and can result in overdose and death (see Overdosage).

Opioid are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing NUCYNTA ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the

proper disposal of unused drug (see Patient Counseling Information). Contact the local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status (see Overdosage). Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of NUCYNTA ER, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression especially within the first 24-72 hours of initiating therapy with and following dosage increases of NUCYNTA ER. To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA ER are essential (see Dosage and Administration). Overestimating the NUCYNTA ER dosage when converting patients from another opioid product can result in fatal overdose with the first dose.

Accidental ingestion of even one dose of NUCYNTA ER, especially by children, can result in respiratory depression and death due to an overdose of tapentadol.

Neonatal Opioid Withdrawal Syndrome Prolonged use of NUCYNTA ER during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for a prolonged period of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available (see Use in Specific Populations, Patient Counseling Information).

Risk from Concomitant Use with Benzodiazepines or Other CNS Depressants Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on NUCYNTA ER therapy. The co-ingestion of alcohol with NUCYNTA ER may result in increased plasma tapentadol levels and a potentially fatal overdose of tapentadol (see Clinical Pharmacology).

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of NUCYNTA ER with benzodiazepines or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics (see Drug Interactions).

If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when NUCYNTA ER is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs (see Drug Interactions and Patient Counseling Information).

Risk of Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of NUCYNTA ER in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

Patients with Chronic Pulmonary Disease: NUCYNTA ER treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of NUCYNTA ER (see Warnings and Precautions).

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients (see Warnings and Precautions).

Alternatively, consider the use of non-opioid analgesics in these patients.

Monitor such patients closely, particularly when initiating and titrating NUCYNTA ER and when NUCYNTA ER is given concomitantly with other drugs that depress respiration (see Warnings and Precautions).

Serotonin Syndrome with Concomitant Use of Serotonergic Drugs Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of tapentadol with serotonergic drugs.

Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic

antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including MAO inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue) (see Drug Interactions). This may occur within the recommended dosage range.

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, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days of concomitant use, but may occur later than that.

Discontinue NUCYNTA ER if serotonin syndrome is suspected.

Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.

Severe Hypotension NUCYNTA ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) (see Drug Interactions). Monitor these patients for signs of hypotension after initiating or titrating the dosage of NUCYNTA ER. In patients with circulatory shock, NUCYNTA ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of NUCYNTA ER in patients with circulatory shock.

Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), NUCYNTA ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with NUCYNTA ER. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of NUCYNTA ER in patients with impaired consciousness or coma.

Risks of Use in Patients with Gastrointestinal Conditions NUCYNTA ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus.

The tapentadol in NUCYNTA ER may cause spasm of the sphincter of Oddi.

Opioids may cause increases in serum amylase. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Increased Risk of Seizures in Patients with Seizure Disorders The tapentadol in NUCYNTA ER may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Monitor patients with a history of seizure disorders for worsened seizure control during NUCYNTA ER therapy.

Withdrawal Avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including NUCYNTA ER. In these patients, mixed agonists/ antagonists and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms (see Drug Interactions).

When discontinuing NUCYNTA ER, gradually taper the dose (see Dosage and Administration). Do not abruptly discontinue NUCYNTA ER (see Drug Abuse and Dependence).

Risks of Driving and Operating Machinery NUCYNTA ER may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery.

Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of NUCYNTA ER and know how they will react to the medication (see Patient Counseling Information).

Risk of Toxicity in Patients with Hepatic Impairment A study with an immediate-release formulation of tapentadol in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Avoid use of NUCYNTA ER in patients with severe hepatic impairment. Reduce the dose of NUCYNTA ER in patients with moderate hepatic impairment (see Dosage and Administration and Clinical Pharmacology). Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression when initiating and titrating NUCYNTA ER. Risk of Toxicity in Patients with Renal Impairment Use of NUCYNTA ER in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known (see Clinical Pharmacology).

ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: • Addiction, Abuse, and Misuse (see Warnings and Precautions) • Life-Threatening Respiratory Depression (see Warnings and Precautions) • Neonatal Opioid Withdrawal Syndrome (see Warnings and Precautions) • Interaction with Benzodiazepine or Other CNS Depressants (see Warnings and Precautions)

• Serotonin Syndrome (see Warnings and Precautions) • Adrenal Insufficiency (see Warnings and Precautions) • Severe Hypotension (see Warnings and Precautions) • Gastrointestinal Adverse Reactions (see Warnings and Precautions) • Seizures (see Warnings and Precautions) • Withdrawal (see Warnings and Precautions) Clinical Trial Experience Commonly-Observed Adverse Reactions in Clinical Studies with NUCYNTA ER in Patients with Chronic Pain due to Low Back Pain or Osteoarthritis The most common adverse reactions (reported by ≥10% in any NUCYNTA ER dose group) were: nausea, constipation, dizziness, headache, and somnolence.

The most common reasons for discontinuation due to adverse reactions in eight Phase 2/3 pooled studies reported by ≥1% in any NUCYNTA ER dose group for NUCYNTA ER- and placebo-treated patients were nausea (4% vs. 1%), dizziness (3% vs. <1%), vomiting (3% vs. <1%), somnolence (2% vs. <1%), constipation (1% vs. <1%), headache (1% vs. <1%), and fatigue (1% vs. <1%), respectively.

Please see full Prescribing Information for ADRs occurring in ≥ 1% of patients.

Commonly-Observed Adverse Reactions in Clinical Studies with NUCYNTA ER in Patients with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy The most commonly reported ADRs (incidence ≥10% in NUCYNTA ER-treated subjects) were: nausea, constipation, vomiting, dizziness, somnolence, and headache.

Please see full Prescribing Information for ADRs occurring in ≥ 1% of patients.

Postmarketing Experience The following adverse reactions have been identified during post approval use of tapentadol.

Psychiatric disorders: hallucination, suicidal ideation, panic attack Serotonin syndrome: Cases of serotonin syndrome, a potentially lifethreatening condition, have been reported during concomitant use of opioids with serotonergic drugs.

Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.

Anaphylaxis: Anaphylaxis has been reported with ingredients contained in NUCYNTA ER. Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids (see Clinical Pharmacology).

DRUG INTERACTIONS Clinically Significant Drug Interactions with NUCYNTA ER Alcohol Clinical Impact:

Concomitant use of alcohol with NUCYNTA ER can result in an increase of tapentadol plasma levels and potentially fatal overdose of tapentadol.

Intervention: Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on NUCYNTA ER therapy.

Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Due to additive pharmacologic effect, the concomitant use of Impact: benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.

Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].

Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.

Serotonergic Drugs Clinical The concomitant use of opioids with other drugs that affect Impact: the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions 5.6].

Intervention: If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment.

Discontinue NUCYNTA ER if serotonin syndrome is suspected.

Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Monoamine Oxidase Inhibitors (MAOIs) Clinical MAOI interactions with opioids may manifest as serotonin Impact: syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].

Intervention: Do not use NUCYNTA ER in patients taking MAOIs or within 14 days of stopping such treatment Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical May reduce the analgesic effect of NUCYNTA ER and/or Impact: precipitate withdrawal symptoms.

Intervention: Avoid concomitant use.

Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Tapentadol may enhance the neuromuscular blocking action of Impact: skeletal muscle relaxants and produce an increased degree of respiratory depression.

NUCYNTA ER (tapentadol) extended-release tablets, CII BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION (continued) Muscle Relaxants (continued) Intervention: Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of NUCYNTA ER and/or the muscle relaxant as necessary.

Diuretics Clinical Opioids can reduce the efficacy of diuretics by inducing the Impact: release of antidiuretic hormone.

Intervention: Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs Clinical The concomitant use of anticholinergic drugs may increase Impact: risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Intervention: Monitor patients for signs of urinary retention or reduced gastric motility when NUCYNTA ER is used concomitantly with anticholinergic drugs.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C Risk Summary Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome (see Warnings and Precautions).

The background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy can occur regardless of the health of the mother or the use of medications.

Clinical Considerations Fetal/neonatal adverse reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight.

Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly (see Warnings and Precautions).

Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psychophysiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. NUCYNTA ER is not recommended for use in pregnant women during and immediately prior to labor. Opioid analgesics, including NUCYNTA ER, can prolong labor.

Lactation Risk Summary There is insufficient/limited information on the excretion of tapentadol in human or animal breast milk. Physicochemical and available pharmacodynamic/toxicological data on tapentadol point to excretion in breast milk and risk to the breastfeeding child cannot be excluded.

Because of the potential for serious adverse reactions including excess sedation and respiratory depression in a breastfed infant, advise patients that breast feeding is not recommended during treatment with NUCYNTA ER. Clinical Considerations Monitor infants exposed to NUCYNTA ER through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.

Females and Males of Reproductive Potential Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.

Pediatric Use The safety and efficacy of NUCYNTA ER in pediatric patients less than 18 years of age have not been established.

Geriatric Use Of the total number of patients in Phase 2/3 double-blind, multiple-dose clinical studies of NUCYNTA ER, 28% (1023/3613) were 65 years and over, while 7% (245/3613) were 75 years and over. No overall differences in effectiveness or tolerability were observed between these patients and younger patients.

Elderly patients (aged 65 or older) may have increased sensitivity to tapentadol. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of NUCYNTA ER slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression (see Warnings and Precautions).

Hepatic Impairment Use of NUCYNTA ER in patients with severe hepatic impairment (ChildPugh Score 10-15) is not recommended. In patients with moderate hepatic impairment (Child-Pugh Score 7 to 9), dosage reduction of NUCYNTA ER is recommended (see Dosage and Administration).

Renal Impairment Use of NUCYNTA ER in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) is not recommended.

DRUG ABUSE AND DEPENDENCE Controlled Substance NUCYNTA ER contains tapentadol, a Schedule II controlled substance.

Abuse NUCYNTA ER contains tapentadol, a substance with a high potential for abuse similar to other opioids including fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, and oxymorphone. NUCYNTA ER can be abused and is subject to misuse, addiction, and criminal diversion (see Warnings and Precautions).

The high drug content in extended-release formulations adds to the risk of adverse outcomes from abuse and misuse.

All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.

“Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers, and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare providers 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 true addiction.

NUCYNTA ER, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

Risks Specific to Abuse of NUCYNTA ER NUCYNTA ER is for oral use only. Abuse of NUCYNTA ER poses a risk of overdose and death. The risk is increased with concurrent use of NUCYNTA ER with alcohol and other central nervous system depressants.

With intravenous abuse the inactive ingredients in NUCYNTA ER can result in local tissue necrosis, infection, pulmonary granulomas, embolism and death, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

NUCYNTA ER should not be abruptly discontinued (see Dosage and Administration). If NUCYNTA ER is abruptly discontinued in a physicallydependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms (see Use in Specific Populations).

OVERDOSAGE Clinical Presentation Acute overdosage with NUCYNTA ER can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases pulmonary edema, bradycardia, hypotension, partial or complete airway obstruction, atypical snoring and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations.

Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed.

Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.

© May 2017, Depomed, Inc. All rights reserved. APL-NUCX-0249

© 2018 Collegium Pharmaceutical, Inc. All rights reserved. PP-NUER-US-0029 02/18

NONPROFIT ORG US POSTAGE PAID BURL VT 05401 PERMIT #19 8700 Monrovia Street, Suite 310, Lenexa, KS 66215

TIME TO DUAL

TW O O NE SOURCES SOURCE

OF PAIN OF RELIEF

NUCYNTA® ER is the first and only FDA-approved long-acting opioid designed to control both nociceptive pain and the neuropathic pain associated with diabetic peripheral neuropathy (DPN).

Not an actual patient.

INDICATIONS AND USAGE NUCYNTA ER (tapentadol) is indicated for the management of: • Pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate • Neuropathic pain associated with diabetic peripheral neuropathy (DPN) severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate

Visit Nucynta.com for more information and to download a NUCYNTA® ER savings card Limitations of Use • Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve NUCYNTA ER for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain • NUCYNTA ER is not indicated as an as-needed (prn) analgesic

IMPORTANT SAFETY INFORMATION WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTION WITH ALCOHOL and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS Addiction, Abuse, and Misuse NUCYNTA ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant can lead to overdose and death. Assess each patient’s risk prior to prescribing NUCYNTA ER, and monitor woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate all patients regularly for the development of these behaviors and conditions. treatment will be available.

Life-threatening Respiratory Depression Interaction With Alcohol Serious, life-threatening, or fatal respiratory depression may occur with use of NUCYNTA ER. Monitor for Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products respiratory depression, especially during initiation of NUCYNTA ER or following a dose increase. Instruct that contain alcohol while taking NUCYNTA ER. The co-ingestion of alcohol with NUCYNTA ER may result in patients to swallow NUCYNTA ER tablets whole; crushing, chewing, or dissolving NUCYNTA ER tablets can increased plasma tapentadol levels and a potentially fatal overdose of tapentadol. cause rapid release and absorption of a potentially fatal dose of tapentadol.

Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Accidental Ingestion Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, Accidental ingestion of even one dose of NUCYNTA ER, especially by children, can result in a fatal overdose including alcohol, may result in profound sedation, respiratory depression, coma, and death. of tapentadol.

• Reserve concomitant prescribing of NUCYNTA ER and benzodiazepines or other CNS depressants for Neonatal Opioid Withdrawal Syndrome use in patients for whom alternative treatment options are inadequate.

Prolonged use of NUCYNTA ER during pregnancy can result in neonatal opioid withdrawal syndrome, • Limit dosages and durations to the minimum required. which may be life-threatening if not recognized and treated, and requires management according to • Follow patients for signs and symptoms of respiratory depression and sedation.

Please see additional Important Safety Information, including BOXED WARNING, and Brief Summary on the adjacent pages.

Nucynta ER is a registered trademark of Depomed, Inc. © 2018 Collegium Pharmaceutical, Inc. All rights reserved. PP-NUER-US-0029 02/18