ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DRUG EVALUATION AND RESEARCH
>
> **ANESTHETIC AND LIFE SUPPORT DRUGS**
>
> **ADVISORY COMMITTEE**
>
> Tuesday, September 9, 2003
>
> 8:10 a.m.
>
> Holiday Inn Bethesda
>
> Bethesda, Maryland
>
> PARTICIPANTS
>
> Nathaniel Katz, M.D., Chair
>
> Johanna Clifford, M.S., RN, BSN, Executive Secretary
>
> MEMBERS
>
> Solomon Aronson, M.D.
>
> Mary Beth Bobek, Pharm D.
>
> Vera Bril, M.D.
>
> Madelyn Kahana, M.D.
>
> Bhupinder Saini, M.D.
>
> Steven L. Shafer, M.D.
>
> Carol Rose, M.D.
>
> VOTING CONSULTANTS
>
> Louis E. Baxter, Sr., M.D.
>
> Domenic Ciraulo, M.D.
>
> Stephanie Crawford, Ph.D., M.S.
>
> John Cush, M.D.
>
> Robert Dworkin, Ph.D.
>
> Jacqueline Gardner, Ph.D., M.P.H.
>
> Jane Maxwell, Ph.D.
>
> Steven Passik, Ph.D.
>
> Russell Portenoy, M.D.
>
> Gregory Skipper, M.D., F.A.S.M.
>
> Brian Strom, M.D., M.P.H.
>
> David J. Wlody, M.D.
>
> VOTING PATIENT REPRESENTATIVE
>
> James Gillett, Ph.D.
>
> NON-VOTING INDUSTRY REPRESENTATIVE
>
> Charles McLeskey, M.D.
>
> NON-VOTING PARTICIPANTS
>
> Laura Nagel, DEA
>
> FDA
>
> Sharon Hertz, M.D.
>
> John Jenkins, M.D.
>
> Deborah B. Leiderman, M.D., M.A.
>
> Robert Meyer, M.D.
>
> Bob Rappaport, M.D.
>
> Victor Raczkowski, M.D.
>
> [C O N T E N T S]{.underline}
>
> [PAGE]{.underline}
>
> Call to Order and Opening Remarks:
>
> Nathaniel Katz, M.D. 5
>
> Introduction of Committee 6
>
> Conflict of interest Statement:
>
> Johanna Clifford, M.S., RN, BSN 11
>
> Opening Remarks:
>
> Bob Rappaport, M.D. 20
>
> **Risk Management of Opiate Analgesics**
>
> FDA\'s Role in the Risk Management of Opiate
>
> Analgesics:
>
> Steven Galson, M.D., M.P.H. 27
>
> Risk Management and the Controlled Substances Act:
>
> the FDA Perspective:
>
> Deborah B. Leiderman, M.D., M.A. 37
>
> DEA\'s Role in Risk Management of Opiate Analgesics:
>
> Terrance Woodworth, M.S. 46
>
> Open Public Hearing
>
> Congressman Harold Rogers 69
>
> Congressman Frank Wolf 79
>
> Opioid Risk: Benefit Contradiction:
>
> Arthur G. Lipman, Pharm. D. 84
>
> Opiate Use Data:
>
> Gianna Rigoni, Pharm. D., M.S. 119
>
> Misuse and Abuse of Opiate Analgesics
>
> in the Medical Setting:
>
> Steven Passik, Ph.D. 136
>
> Nonmedical Use of Pain Relievers: Data from
>
> the National Survey on Drug Use and Health:
>
> Joe Gfroerer 174
>
> Data on Treatment Admissions for Opiate Use:
>
> Deborah Trunzo 185
>
> Opiate Abuse Data:
>
> Judy Ball, Ph.D., M.P.A. 196
>
> Diversion of Prescription Opiates:
>
> Elizabeth Willis, Ed.D. 221
>
> [C O N T E N T S]{.underline} (Continued)
>
> Open Public Hearing
>
> Barry Eliot Cole, M.D. 252
>
> Jeffery Ebel, M.D. 258
>
> Art Van Zee, M.D. 261
>
> Siobhan Reynolds 265
>
> Gregory Walter, M.D. 271
>
> Mary Baluss 272
>
> Bruce Canaday, M.D. 276
>
> Arthur H. Horn, M.D. 281
>
> Jan Towers, Ph.D. 285
>
> David E. Joranson, M.D. 290
>
> Daniel B. Carr, M.D. 300
>
> **Existing Risk Management Plans**
>
> Introduction: Goals of Risk Management Plans
>
> Non-Opiate Risk Management Plans:
>
> Anne Trontell, M.D., M.P.H. 306
>
> Current Opioid Risk Management Plans:
>
> Celia Winchell, M.D. 330
>
> Committee Discussion 354
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Call to Order and Opening Remarks**
>
> DR. KATZ: Good morning. Welcome to the meeting of the Anesthetic and
> Life Support Drugs Advisory Committee the purpose of which will be to
> advise the FDA on risk management programs for opioid analgesics, in
> particular modified-release products.
>
> My name is Nathaniel Katz. I will be chairing the meeting this
> morning, and my job will be to make sure that we succeed in providing
> all of the relevant input that has been asked to this division of the
> FDA.
>
> To my right is Johanna Clifford. She is actually the real person who
> is running the meeting, and her job is to make sure that I do my job
> and that the meeting stays on track.
>
> Now, the Division has worked very hard to create a truly
> interdisciplinary group of individuals representing many of the
> relevant stakeholders on this issue. While I have a number of ground
> rules for the committee that I would like to go over, what I would
> like to do first is begin with introductions. There are a new people
> on the committee and many invited guests. We don\'t all know each
> other, so I would like to start with taking a minute for us all to
> introduce ourselves.
>
> Let me just remind people from the government that many of us don\'t
> know what the specific committee or agency that you are involved with
> does, so it would also be appropriate for you to take a sentence or
> two to describe, not only who you are, but the place that you are
> from.
>
> Why don\'t we begin at that corner, Dr. Jenkins.
>
> **Introduction of Committee**
>
> DR. JENKINS: Good morning. I am John Jenkins. I am the Director of the
> Office of New Drugs at the Food and Drug Administration. My office is
> responsible for all the divisions that review and approve new drugs.
>
> DR. MEYER: Dr. Bob Meyer. I am the Director of the Office of Drug
> Evaluation II in the Center for Drugs, and my office has the Division
> of Anesthetics, Critical Care, and Addiction Drug Products within it.
>
> DR. RAPPAPORT: Good morning. I am Bob Rappaport. I am the Director of
> the Division of Anesthetics, Critical Care, and Addiction Drug
> Products.
>
> DR. HERTZ: Good morning. I am Sharon Hertz. I am the Medical Team
> Leader for the Analgesic Group in the Division of Anesthetics.
>
> DR. LEIDERMAN: I am Dr. Deborah Leiderman. I direct the Controlled
> Substances staff within the Office of the Center Director. In CDER, we
> are responsible for all aspects of abuse liability assessment and
> interface with other federal agencies around issues of abuse and drug
> scheduling.
>
> DR. RACZKOWSKI: Good morning. My name is Victor Raczkowski. I am the
> Director of the Office of Drug Safety in the Center for Drugs. Our
> office is heavily involved in risk assessment, risk communication,
> risk management, and medication errors. We work closely with the
> Office of New Drugs both before and after approval to ensure drugs
> appropriate use.
>
> MS. NAGEL: My name is Laura Nagel. I am from the Drug Enforcement
> Administration, Office of Diversion Control. We are responsible for
> the enforcement of the Controlled Substance Act particularly as it
> pertains to legitimately manufactured drugs.
>
> DR. CRAWFORD: Good morning. My name is Stephanie Crawford. I am from
> the University of Illinois at Chicago, College of Pharmacy. I am a
> guest participant from the Drug Safety and Risk Management Advisory
> Committee.
>
> DR. SHAFER: Steve Shafer, Professor of Anesthesia, Stanford
> University.
>
> DR. BAXTER: Lou Baxter. I am Executive Medical Director of Medical
> Society of New Jersey, Physicians Health Program, and I am brand new.
> I am here and that is about all that I can tell you.
>
> DR. GARDNER: I am Jacqueline Gardner, the University of Washington
> School of Pharmacy, and I also am from the Drug Safety and Risk
> Management Committee.
>
> DR. ARONSON: Solomon Aronson. I am the Chief of the Anesthesiology
> Services for Vanguard Health Systems in Chicago.
>
> DR. SAINI: Bhupinder Saini. I am an anesthesiologist by background. I
> practice full-time pain management. I am president of a 12-man group
> who are totally dedicated to pain management.
>
> DR. KAHANA: I am Madelyn Kahana. I am a Professor of Anesthesiology,
> Pediatrics, and Critical Care Medicine at the University of Chicago.
>
> MS. CLIFFORD: Good morning. I am Johanna Clifford. Nat already
> provided you with my job description. I will be the Exec Sec to this
> meeting.
>
> DR. BRIL: Good morning. I am Vera Bril. I am a Professor of Medicine
> at the University of Toronto with an interest in neuromuscular
> disorders. I am a member of the Advisory Committee.
>
> DR. ROSE: Good morning. I am Carol Rose. I am an Assistant Professor
> of Anesthesiology at the University of Pittsburgh School of Medicine
> and University of Pittsburgh Medical Center. I am a clinical
> anesthesiologist.
>
> DR. WLODY: Good morning. My name is David Wlody. I am academic
> anesthesiologist at the State University of New York Downstate Medical
> Center. I am a consultant to the committee.
>
> DR. PASSIK: Steve Passik. I am a clinical psychologist and I direct
> the Palliative Care program at the Markey Cancer Center at the
> University of Kentucky.
>
> DR. DWORKIN: Hi. I am Bob Dworkin. I am a Professor in the Department
> of Anesthesiology at the University of Rochester in upstate New York.
>
> DR. CUSH: Good morning. I am Jack Cush. I am Chief of Rheumatology and
> Clinical Immunology at the Presbyterian Hospital of Dallas and the
> University of Texas Southwestern Medical School in Dallas. I am here
> representing the Arthritis Advisory Committee.
>
> DR. BOBEK: Good morning. I am Mary Beth Bobek. I am the consumer
> representative. I am also Clinical Faculty at University of North
> Carolina College of Pharmacy.
>
> DR. SKIPPER: I am Dr. Greg Skipper. I am an internist and addiction
> medicine specialist on the faculty at the University of Alabama at
> Birmingham. I am also the Medical Director of the Physician Health
> Program in Alabama. I am here for the Drug Abuse Advisory
> Subcommittee.
>
> DR. CIRAULO: I am Dom Ciraulo. I am Chairman of Psychiatry at Boston
> University School of Medicine. I am also on the Drug Abuse Advisory
> Subcommittee. I have had a long-standing interest in developing
> clinical pharmacology laboratory paradigms for abuse liability.
>
> DR. MAXWELL: I am Jane Maxwell. I am a research professor at the
> University of Texas at Austin and on the Drug Abuse Subcommittee.
>
> DR. STROM: I am Brian Strom. I am Professor and Chair of Biostatistics
> and Epidemiology, although I am not a biostatistician, I am an
> epidemiologist, and I am from the Drug Safety and Risk Management
> Committee.
>
> DR. GILLETT: Good morning. I am Jim Gillett. I am Professor of
> Ecotoxicology and Director of Graduate Studies in Risk Analysis and
> Cornell University. I am here as patient representative, as President
> of Esophageal Cancer Awareness Association.
>
> DR. McLESKEY: Charlie McLeskey. I am the industry representative on
> this committee, and I am an anesthesiologist employed at Abbott
> Laboratories, Global Medical Director for Anesthesia and Sedation
> Products.
>
> DR. KATZ: Thank you, everybody.
>
> Ms. Clifford will read the Conflict of Interest Statement.
>
> **Conflict of Interest Statement**
>
> MS. CLIFFORD: The following announcement addresses conflict of
> interest issues with respect to this meeting and is made a part of the
> record to preclude even the appearance of impropriety at this meeting.
>
> The topics to be discussed today will not focus on any particular
> product or company, but rather may affect those companies that make or
> are developing modified-release opiate analgesic drug products.
>
> The conflict of interest statutes prohibit special Government
> employees from participating in matters that could affect their own or
> their employer\'s financial interests.
>
> All participants have been screened for interests in the products and
> companies that could be affected by today\'s discussions.
>
> In accordance with 18 United States Code section 208(b)(3), the Food
> and Drug Administration has granted waivers to the following
> individuals because the Agency has determined that the need for their
> services outweighs the potential for a conflict of interest. They are:
> Dr. Nathaniel Katz, Dr. Robert Dworkin, Dr. Steven Shafer, Dr. Steven
> Passik, Dr. Russell Portenoy.
>
> A copy of the waiver statements may be obtained by submitting a
> written request to the Agency\'s Freedom of Information Office, Room
> 12A-30 of the Parklawn Building.
>
> We would also like to note that Dr. Charles McLeskey is participating
> as a non-voting industry representative, acting on behalf of regulated
> industry. Dr. McLeskey is an employee of Abbott Laboratories and is a
> shareholder.
>
> With respect to FDA\'s invited guests, there are reported interests
> that we believe should be made public to allow the participants to
> objectively evaluate their comments.
>
> Dr. Arthur Lipman has consulted for Purdue Pharma and Endo
> Pharmaceuticals. In recent years, he has received support from
> literally all the analgesic manufacturers through unrestricted
> educational grants and through speakers\' bureaus.
>
> In the event the discussions involve products or firms not on the
> agenda for which an FDA participant has a financial interest, the
> participants are aware of the need to exclude themselves from such
> involvement and their exclusion will be noted for the record.
>
> With respect to all participants, ask in the interest of fairness that
> they address any current or previous financial involvement with any
> firm whose products they may wish to comment upon.
>
> In addition, we have received a number of letters from the public.
> These have been provided to the committee and are available for
> viewing today at the registration desk, and they will be made part of
> the public record, as well.
>
> DR. KATZ: Thank you, Johanna.
>
> Since many around the table are new to the Advisory Committee process,
> I wanted to take a minute or two to provide an orientation and to give
> a charge to the committee for our work task for the next two days.
> Right after that we will go to Dr. Rappaport\'s opening comments.
>
> First of all, just to briefly summarize\--and many of our other
> speakers will go into this in great detail\--why we are here.
>
> The purpose of this meeting is because it has been recognized that
> opioids are essential in the management of patients with chronic pain,
> but yet that they are associated with risks, so that individuals and
> sponsors have proposed risk management programs in order to diminish
> those risks while not interfering with appropriate medical management.
>
> So, our task here today will be to advise this Division of the FDA and
> give them feedback on the pros and cons of various risk management
> approaches that have been proposed, both in general today, and
> tomorrow with respect to a particular product called Palladone.
>
> One of the first points I would like to make is that approval of any
> drug is a complicated process that depends upon a lot more than just
> the risk management plan, so I would like to make it clear from the
> outset that whether Palladone should or should not be approved will be
> beyond the scope of our discussion both today and tomorrow. What we
> will be focusing on is just one component of information relevant to
> that, which is the risk management program itself.
>
> The two days will be divided into two different sorts of activities.
> The first will be lectures with a little bit of question and answer,
> and that will really occupy most of today. Then, there will be some
> time for discussion today and then tomorrow, there will be a large
> chunk of time for discussion of issues that come up both today
> tomorrow. That discussion will be structured in the form of questions
> which everybody around the table should have received and may have had
> a chance to look at by now.
>
> Now, my own experience, this is the second Advisory Committee meeting
> that I have chaired that relates to opioids, and my own experience
> both here and elsewhere is that opioids may be more be, more than many
> other areas of medicine, seem to create a lot of excitement and
> passion among the people involved in the discussion.
>
> So, what I would like to do is to create a sense of collaboration of
> the people around the table. Since this is an informational meeting,
> it is not a requirement that we all come to consensus or agree with
> each other or persuade each other about our different perspectives,
> and furthermore, our different perspectives may be very true, but may
> be only true for the sorts of patients that we see or the particular
> area that we practice in or the sort of training that we come from or
> all sorts of other biases that we bring to the table.
>
> So, our job today will be to not necessarily come to any consensus
> with definitive answers and everything, but at least to illuminate
> where there are different schools of thought, to outline the evidence
> based behind different perspectives on this issue, and to share the
> information and perspectives, so that the division can go back with
> all this information and make decisions that day I need to make.
>
> So, what will work well for us around the table will be to focus
> primarily on the content issues. What tends not to work as well is
> when folks like us start saying that this government agency ought to
> do this or that one ought to do that since training and the exact
> scope and authority of different government agencies is certainly
> beyond my expertise and probably beyond the expertise of many folks
> around the table. So, we are here to provide content information and
> hopefully, our collaboration will illuminate this issue more to an
> extent that will be helpful to the division.
>
> Now, as far as practical details, though, there are a few practical
> things I just want to let you know about. In order to speak, the
> procedure is if you just raise your hand, Johanna will write your name
> down and we will try to go in more or less a first come-first serve
> way, but there are times where it will be important for me to violate
> that rule and try to foster particularly discussion that might seem
> productive, so don\'t feel like you are being discriminated against if
> you raise your hand next, but I am not calling on your next.
>
> However, sometimes things come up where I can\'t see you, particularly
> the people in these corners are sometimes hard to see, so if you do
> feel that for some reason, we have not been recognizing you
> appropriately, just grab myself or Johanna during the break.
>
> When you go to speak, turn on your microphone and when you are done
> speaking, turn off your microphone unless you want all of your little
> comments to the side to be heard by everybody.
>
> There will be a very helpful system for speakers, as well as for
> people in the open public forum, and that system is called a red
> light. I will tell you more about that when the time comes. For
> speakers who are getting up, there will be both a yellow light and a
> red light, so the yellow light, if you are up speaking at the podium,
> the yellow light will come on two minutes before you are ready to
> stop.
>
> Now, there has been no time for question and answer built into the
> lecture, so if you want to have people to have the opportunity to ask
> questions and to have a dialogue, when your yellow light comes on,
> stop then and that will give about two minutes for a couple of quick
> questions and answers. Obviously, there will be ample time for
> discussion later.
>
> When your red light comes on, then, you are done. So, what I really
> want to do is apologize to all the speakers in advance, because I will
> cut you off when that red light comes on, so don\'t take it
> personally, it\'s just for the purpose of making sure that we get our
> job done over the next two days, and I will cut people off equally and
> fairly when that red light comes on.
>
> Another issue is that people around the table may have questions for
> people also around the table or for speakers or for other people
> sitting around the table. If you do have any questions, then, the
> protocol is just go through me, so raise your hand, I will address
> you, and if you have a question, just let me know and depending on how
> the meeting is flowing, we will see if we can pose those questions to
> other folks around the table.
>
> If there is anything we can do to make you more comfortable, let us
> know.
>
> I think those were all my procedural comments.
>
> With that, let me introduce Dr. Bob Rappaport, who, as he said, is
> Division Director of the Anesthetic, Critical Care, and Addiction
> Products Division, who will give us opening comments.
>
> **Opening Remarks**
>
> DR. RAPPAPORT: Thank you, Dr. Katz.
>
> Good morning. Dr. Katz, members of the committee, invited guests, I
> would like to thank you at the outset of this meeting for your
> participation. You will be addressing an important public health issue
> during this session - how do we approach the issue of prescription
> opiate abuse while assuring the proper treatment of pain.
>
> Prescription drug abuse is a growing problem in this country and
> opiate analgesics are some of the most widely abused and misused
> prescription products available today, however, one of the very
> reasons that these products have become widespread in use and
> availability is that for the first time in modern history, the
> appropriate treatment of chronic pain is receiving the acceptance and
> the recognition in the medical community that it so urgently deserves.
>
> Tens of millions of Americans are estimated to suffer from chronic
> pain. Many of those people are appropriately treated with opiate
> analgesics and for many that treatment will provide them with relief
> from suffering and the possibility of returning to a normal life in a
> manner that is not currently available with non-opiate treatments.
>
> Therein lies a conundrum, opiates are abused and because they are
> abused, some prescription opiates are diverted and the more potent
> modified-release products that are available today are of particular
> interest to abusers, not only to the seasoned addict and those that
> hope to profit from human frailty, but also to the teenager who wants
> to experiment with these intriguing potions and yet may die after a
> single large exposure.
>
> In our role as public health advocates, the increasing incidence of
> abuse, addiction and overdose in this country must concern us. These
> potent modified-release products are potentially dangerous even in
> legitimate medical practice when their unique pharmacokinetic and
> pharmacodynamic characteristics are not fully understood.
>
> Overdose and death and patients being converted from one high potency,
> high-dose opiate to another and inappropriate use by inexperienced
> physicians must concern us.
>
> Chronic pain is still undertreated in millions of patients.
> Misconceptions about the normal physiological dependence that occurs
> with opiate analgesic treatment and its role in addiction abound.
> Irrational fears based on myth and lore often interfere with the
> proper treatment of the patients most in need. Chronic pain claims a
> huge toll on individuals and on the American economy, and this must
> concern us.
>
> How can we intervene to reduce prescription opiate abuse, assure safe
> use in the medical setting, and yet assure appropriate access to
> patients with chronic pain who need opiates for proper treatment? Risk
> management interventions have been touted as one of the potential
> solutions to this perplexing dilemma.
>
> The Agency has implemented risk management plans for other drug
> products and we will attempt to familiarize you with the scope and the
> range of those plans today.
>
> We have reviewed a number of risk management plans for extended
> release opiate analgesics that we will also describe to you, which
> elements of risk management work and which don\'t, which elements
> might even have a counterproductive effect.
>
> For the most part, that sort of data may not even exist. Do we even
> know the proper methodology for collecting the data? In fact, these
> are the very questions that we will pose to you over the next two
> days.
>
> We have assembled some of the leading experts both from the government
> and from academic to review the extent of the problem for you. You
> will hear from SAMHSA representatives about the data they have
> collected on prescription opiate abuse and from the FDA Office of Drug
> Safety on the current medical usage data for these products.
>
> Representatives from the DEA will describe their role in diversion
> control and risk management and their perspective on the problem of
> opiate analgesic diversion. The FDA Controlled Substance staff will
> outline the Agency\'s authority and responsibility under the
> Controlled Substances Act, and the Deputy Director of the Center for
> Drug Evaluation and Research will define the challenge of risk
> management for long-acting opiate analgesics under the authority of
> the Food, Drugs, and Cosmetics Act.
>
> In addition, experts in the medical use of opiate analgesics and their
> misuse in the medical setting will present the most recent information
> from the clinical academic community on the benefits and challenges
> that are inherent in the use of these products.
>
> As this meeting is centered on the development of risk management
> plans for opiate analgesics, you will also hear from the Agency\'s
> drug safety staff and the New Product Review staff regarding the
> existing risk management plans for both opiate analgesics and other
> drug products.
>
> We will define the elements of these plans for you and ask you to help
> assess their value, reliability, and inherent risks. We will ask you
> to address what role education, restricted access, surveillance, and
> other elements may play in the risk management of prescription opiate
> use, how might these elements be implemented, how can their success or
> failure be measured, where might those elements aimed at lessening
> diversion and misuse be in conflict with appropriate patient care, and
> what research projects should be considered to inform these programs.
>
> Finally, during the open public hearing, there will be an opportunity
> for experts, advocates, concerned citizens, and most importantly,
> patients from both the pain and addiction populations to speak to you
> about their experiences and about their concerns.
>
> Tomorrow, we will discuss a specific risk management plan.
> Representatives from Purdue Pharma will review the basis for their New
> Drug Application for Palladone and extended release hydromorphone
> product.
>
> They will focus their presentation on their proposed risk management
> plan for Palladone and provide data in support of that plan from a
> similar plan that has been designed for their other extended release
> opiate analgesic drug product OxyContin.
>
> The Agency\'s Controlled Substances staff will provide their
> perspective on the abuse liability of Palladone and Dr. Mary Jeanne
> Kreek will provide a broader perspective in her discussion on the
> challenges of pharmacotherapy with long acting opiates.
>
> You will then be asked to provide the FDA staff with recommendations
> regarding the Palladone risk management plan. It is important to
> recognize that formal risk management for pharmaceuticals is still a
> young endeavor. There are no well traveled paths to follow.
>
> As experts in the treatment of pain, in the treatment and epidemiology
> of abuse and addiction, and in risk management strategy and
> communication, we are hopeful that you will provide us with guidance
> and direction as we attempt to find new paths towards reasoned and
> sustainable solutions to a difficult and complex problem.
>
> We know that the FDA cannot hope to implement or sustain any solution
> to this problem by itself. It will be of paramount importance for you
> to keep in mind that there are many stakeholders in this effort -
> other government agencies, the academic community, the pharmaceutical
> industry, the clinical community, and the patients and their
> caregivers and families.
>
> Each of these has important, but often differing perspectives and
> differing roles, however, as individuals and as members of
> organizations and communities, we must all share in the work ahead, so
> that we may all share in the rewards.
>
> Once again, I would like to thank you for being generous with your
> time and expertise by participating in this important meeting.
>
> DR. KATZ: Thank you, Dr. Rappaport.
>
> I would like to now introduce Dr. Steven Galson, who is the Deputy
> Center Director of the Center for Drug Evaluation and Research, and
> who will be speaking with us about the FDA role in the risk management
> of opiate analgesics.
>
> **FDA\'s Role in the Risk Management**
>
> **of Opiate Analgesics**
>
> DR. GALSON: Thank you very much. I am extremely happy to be here this
> morning and I want to start by thanking the members of the committee
> and the Chair for your sense of public purpose and commitment in being
> here. I know we can\'t really compensate you for your time, you are
> all very, very busy.
>
> We will rely very heavily on your clear-eyed and objective answers to
> the questions that we pose to you in making our decisions about steps
> to take regarding this group of products and the product that you are
> hearing about tomorrow. So, again thank you very much.
>
> \[Slide.\]
>
> I am here today to talk about the FDA\'s role in the risk management
> of opiate analgesics and I want to start by taking you back to the
> very beginning. This is review for a lot of you, I will go fairly
> quickly, but just so that you understand clearly what the role of the
> Agency is.
>
> The Food, Drug, and Cosmetic Act tells us that we can require from
> drug applicants, from sponsors, tests that are reasonably applicable
> to show whether or not these drugs are safe for use under the
> conditions for which the application is designed.
>
> \[Slide.\]
>
> But what does drug safety mean? No drug is 100 percent safe, all drugs
> have risks. We all know that.
>
> We define based on the requirements of the Food, Drug, and Cosmetic
> Act that the benefits of the drugs that we approve outweigh the
> foreseeable risks for the specific indication, the medical indication,
> and for the specific population for which they are designed.
>
> \[Slide.\]
>
> We use a large variety of tests to assure this. We require nonclinical
> studies of laboratory animals, a lot of human data, which I will focus
> on very quickly in a second. We also don\'t keep the requirements
> static. We incorporate new science when it has been demonstrated to
> help us in assisting our reviewers to look at safety and efficacy
> about the products in front of us.
>
> We are continually using new information and we are not standing
> still.
>
> \[Slide.\]
>
> With regard to human data, we applications for drugs that have been
> exposed to approximately 10,000 people for varying duration and
> dosing. The people who take these drugs in clinical trials frequently
> have other concurrent illnesses.
>
> We have the statistical power to detect an association for an event
> occurring 1 in 100 to 1 in 1,000 people depending on the background
> rate of that condition. We don\'t have capacity in the methods that we
> currently use to review and approve drugs of detecting and
> quantitating very infrequent events more rare than noted there.
>
> \[Slide.\]
>
> For predicting the benefit, we use randomized, controlled trials, as
> you all know. These, however, lack generalizability to populations
> that were not participants in the controls, the larger society, and,
> as well, these clinical trials don\'t study all domains of benefit.
>
> There may be nonquantifiable, but very important benefits to patients
> that aren\'t quantified in these studies, and we also can\'t predict
> in these studies the uncertainties of certain kinds of use and
> certainly not the uncertainties of abuse.
>
> \[Slide.\]
>
> So, before we approve a drug, we are assured that the benefit
> outweighs the risks, as you see in this simple chart.
>
> \[Slide.\]
>
> But there are lots of things that can happen after a drug is approved.
> Certainly, abuse, as you all know about, we may not have done a good
> job of predicting the risk for a variety of reasons, that some of
> these risks may have been unpredictable.
>
> There may be errors involved in the way the drug is used, committed
> both by patients or by participants in the healthcare system, or there
> may be inherent risks with the drugs. We know, as I said before, that
> all drugs have risks, and these inherent risks may be more important
> than we had anticipated.
>
> \[Slide.\]
>
> Therefore, we know a drug is less safe and if it is used in a way that
> decreases the foreseeable benefit and if it is used in a way or in a
> way that increases risk of if the actual risks are greater than the
> predicted risks. There are a lot of different things that can, quote
> \"go wrong.\"
>
> \[Slide.\]
>
> Getting more specific to the products you are interested in here,
> moving towards that, our goal in managing risk is to look at it
> throughout the product life cycle. We begin this in drug review and
> approval process through the methods that I have just talked about,
> and we use multiple risk management tools, such as the language in the
> drug label that is distributed with the drugs, restrictions on use of
> the drug or on the distribution or other special requirements to try
> to assure that the risks of the drug are maintained in a manageable
> way throughout the life cycle.
>
> This process continues after drugs are approved. I don\'t have time to
> go into a lot of detail about this, but we conduct passive
> surveillance with our adverse event reporting system where
> practitioners, patients, and others can send reports in when they
> notice them to the Agency. We keep track of those, collate them, and
> look at them very carefully.
>
> There are lot of other systems to look at the safety of drugs that are
> on the market including four opiates, just as an example, here the
> Drug Abuse Warning Network, which is not run by the FDA, but detects
> increases in reports through emergency rooms of drug abuse problems.
>
> We can also conduct special studies when we are concerned about a
> particular problem with the drug, and others in the medical community
> and in the research community conduct these studies for us, or may
> conduct them for other reasons, and we look at them to weigh all of
> these pieces of information after a drug is approved.
>
> \[Slide.\]
>
> So, we conduct periodic evaluation of risks and benefits of drugs that
> are on the market if the use changes beyond what we had anticipated,
> if new risk-benefit data come up through the scientific process or
> through another means, or if for some reason we are aware that our
> risk management steps have not been effective enough.
>
> In those cases, we may make changes in the way that the drug is
> labeled or in other aspects of the way the drug is used and
> distributed in consultation with the drug sponsors, but these changes
> have to be consistent with our statutes and with our regulations.
>
> We are watched very closely in those regards, and we have a limited
> number of degrees of freedom that we can go in making changes to drugs
> once they are approved.
>
> We also, as I think you all know, enforce advertising regulations
> which can be very important for this group of compounds. We also
> coordinate with other federal agencies, particularly with DEA, around
> the opiates, or other organizations to try to control risk, to try to
> work to mitigate information which may be incorrect about these
> compounds.
>
> \[Slide.\]
>
> In the special case of opiate analgesics, which you are here to talk
> about today, we know that these drugs are a very important part of our
> medical arms chest. They are safe and effective when used properly,
> but we do have indications that there have been increases in
> opiate-related abuse and deaths, and that is one of the reasons that
> you are here.
>
> The Federal Government regulatory authority and responsibility for
> risk management for this group of drugs is shared with the Drug
> Enforcement Administration, with the FDA being responsible for the
> items that I have talked about previously, and the DEA responsible for
> enforcing the regulations and the laws to reduce abuse, and you are
> going to hear about that from DEA speakers later in this meeting.
>
> \[Slide.\]
>
> What are our challenges in risk management of this group of drugs in
> 2003? We need to maintain a positive risk-benefit balance, as I have
> been talking about. We need to maintain access for the patients who
> need these drugs, and we want to be able to use the label that we
> approve for these drugs appropriately to foster risk management.
>
> We need to base our decisions about changes and approval of these
> drugs on science, not on emotion, and we need to base them on what we
> can assess to be the current medical practice consensus. That is why
> you are here, that is why you represent different parts of the medical
> community, and as you know, a lot of medical groups have been working
> on trying to assess what the right way to use opiate analgesics for
> many, many years, there has been a lot of consensus work done in
> medical organizations, and we need to pay very close attention to that
> because the medical community and the healthcare community is really
> one of our most important stakeholders in the Agency.
>
> We can also consider other risk management steps, unusual risk
> management steps, things that haven\'t been tried before.
>
> \[Slide.\]
>
> What is the context under which we are asking you to be here today?
> The problem of opioid abuse is a complex societal problem with a lot
> of different causes. As you know, as scientists, any complex problem
> demands a complex solution. There is not a simple solution to this
> problem.
>
> It is a combination of regulation, public policy, education, and
> research, which is being applied and which continues to need to be
> applied to this problem. We all recognize that it is not going to be
> solved overnight and will only be solved by an incremental improvement
> in how we manage these risks.
>
> As I have mentioned, addressing the problem is the shared
> responsibility of not just the Federal Government, but of other
> agencies, not just the regulatory agencies, but other federal
> agencies, some of which are represented here, the Substance Abuse and
> Mental Health Administration, and the part of the NIH, NIDA, that
> handles drug abuse research, State and local governments, teachers,
> parents, nongovernmental organizations, religious groups, the Boy
> Scouts, et cetera. This is a societal problem, and that is the context
> in which we want you to look at the questions that we are asking you
> today.
>
> Thank you very much again for being here. We look forward to your
> advice, and good luck for a good meeting.
>
> My yellow light isn\'t on, so I can take any questions if folks have
> them based on my comments, otherwise, we will move on.
>
> DR. KATZ: Does anybody around the table have any questions for Dr.
> Galson?
>
> \[No response.\]
>
> DR. GALSON: Thank you very much.
>
> DR. KATZ: Thank you very much.
>
> Before we go on to our next speaker, there is a new person at the
> table who missed the introductions earlier, so, Dr. Portenoy, would
> you like to take half a minute and tell us who you are?
>
> DR. PORTENOY: Thank you. I am sorry about being late, you know, D.C.
> traffic.
>
> I am Russ Portenoy. I chair the Department of Pain, Medicine, and
> Palliative Care at the Beth Israel Medical Center in New York City.
>
> DR. KATZ: Our next speaker will be Dr. Deborah Leiderman. She is the
> Director of the Controlled Substance staff at FDA, as you all heard.
> She will be speaking with us about Risk Management and the Controlled
> Substances Act: the FDA Perspective.
>
> **Risk Management and the Controlled Substances Act:**
>
> **The FDA Perspective**
>
> DR. LEIDERMAN: Good morning.
>
> I will be talking about risk management and the Controlled Substances
> Act through the lens of the FDA. Now, Dr. Galson has outlined the
> general framework of risk management that CDER utilizes, the Center
> for Drugs and FDA utilize.
>
> In advance, I want to acknowledge that my comments about drug control
> and drug scheduling are from the perspective of the FDA, and that the
> DEA will be speaking in greater detail about some of the law and roles
> that I am addressing later in the meeting.
>
> \[Slide.\]
>
> The Controlled Substances Act of 1970, which I will refer to from
> hereon in as the CSA, was enacted to comply with international
> treaties, as well as to address issues of international drug
> trafficking and to assure the availability of legitimate drugs for
> medical use.
>
> The CSA established five schedules and level of control, C1 through 5.
> The major drug classes that are regulated by the CSA are the opioids,
> depressants, stimulants, and hallucinogens.
>
> \[Slide.\]
>
> Under the CSA, Schedule I is the most restrictive. It is reserved for
> drugs with the highest abuse potential and no recognized medical use.
> Examples of drugs within this class include heroin and LSD.
>
> Schedules II through V are used for drugs that have medical use in the
> United States and have, in descending order, levels of abuse potential
> and restrictiveness, II being the highest of medically approved drugs
> and V the lowest.
>
> \[Slide.\]
>
> The subject of today\'s meeting, of the two-day meeting, are, of
> course, the Schedule II opioid analgesics. Now, these drugs have the
> highest potential for abuse. Abuse potential is defined under the CSA,
> placement in Schedule II, means the risk is comparable to that of CI
> drugs. The distinction again is the medical use.
>
> Thus, these drugs are subject to the highest level of control and, by
> definition, pose the greatest risk to the public health.
>
> \[Slide.\]
>
> I think, as Dr. Galson suggested, that we have to look at the use of
> any drug, but certainly the Schedule II opioid analgesics in the
> context of the larger healthcare system and the society.
>
> Certainly, healthcare, the society have changed dramatically since
> enactment of the CSA. Advances in science, medicine,
> pharmacotherapeutics information have changed, and it can be argued
> that what was previously relatively limited, acute disease, often
> terminal, has been transformed into chronic illness. Thus, the CII
> drugs, the opiate analgesics, which 30 or 40 years ago, the use was
> primarily confined to the hospital setting, the operating room, and
> the inpatient ward, have been moved, as has much medical care, into
> the outpatient setting.
>
> \[Slide.\]
>
> The Schedule II opioid analgesics that we are primarily concerned
> with, oxycodone, morphine, fentanyl, hydromorphone, again are all
> Schedule II under the CSA.
>
> Now, the Schedule II designation applies to all strengths and dosage
> forms of each drug. The Controlled Substances Act and the scheduling
> designation does not differentiate between a 5 mg oxycodone and a 160
> mg OxyContin, between an injectable hospital use fentanyl formulation
> and the 2 mg patch. A morphine 5 mg tablet is the same Schedule II as
> the methylphenidate 5 mg tablet.
>
> Schedule II, thus, encompasses a broad range of drug dosages and
> potency, and as we will see, a broad range of drug classes.
>
> \[Slide.\]
>
> Now, this figure is intended to illustrate the range of drug classes,
> as well as dosages and formulations. As you can see, the opiates on
> the left are all in yellow, the barbiturates are in lavender, and the
> stimulant drugs, on the right, are in red. Again, we can see that
> there are intravenous, transdermal, oral formulations in the opiate
> class, and that the range of strengths is quite large.
>
> \[Slide.\]
>
> Just for comparison, looking at the range of drugs controlled under
> Schedules III through V, we see that some of the less potent opioids,
> also in yellow here, are placed in Schedules III, IV, and V, and that
> depressants, stimulants, and other drugs, again a range of
> pharmacologic classes, are controlled under Schedules III through V.
>
> \[Slide.\]
>
> What does it mean for a drug to be controlled under Schedule II?
> Again, the DEA will go into this in much greater detail, but from our
> perspective, manufacturing quotas are established by the DEA with
> input on medical need from the FDA.
>
> Distribution is tracked. There are import and export controls,
> prescribers and dispensers of Schedule II drugs must be registered,
> and Schedule II designation does not permit refills. That is a federal
> law, will not vary across states.
>
> \[Slide.\]
>
> What Schedule II does not require: physician or practitioner
> education, limits on the drug quantity prescribed or dispensed, nor
> does the CSA make any provision for or Schedule II designation mean
> that there will be any prescription monitoring.
>
> \[Slide.\]
>
> This is a schematic of all the parties that play a role in the
> regulation of controlled substances. The two federal agencies that
> FDA, in the left lower corner, and the DEA, with the Scales of Justice
> in the middle, both regulate the manufacture in the upper left corner.
>
> The FDA, of course, is responsible for drug review, approval, and
> labeling. The DEA established quotas and registers manufacturers. Both
> federal agencies have responsibilities with respect to different
> aspects of inspection and compliance.
>
> The state regulatory authorities, which are represented by the
> multicolored figure of the country\--there is no significance to my
> knowledge of the particular color scheme, it is provided by
> Microsoft\--state regulatory authorities regulate prescribers and
> dispensers through licensure.
>
> The DEA also licenses prescribers and dispensers. We can see that
> patients and the community, represented in the right lower corner, and
> I have shown this with a dotted line because they are, in fact, not
> regulated. Prescribers and dispensers interact with the patients and
> the community, but essentially, they are out of the regulatory loop,
> that is, the federal and state regulatory loop.
>
> \[Slide.\]
>
> Again, just to briefly compare and differentiate DEA\'s role from
> FDA\'s role and the state role. DEA registers drug manufacturers,
> establishes quotas, and registers dispensers and prescribers. It does
> not have a role in prescriber education, any knowledge assessment of
> the registered prescribers or dispensers, and it does not ensure
> active surveillance.
>
> \[Slide.\]
>
> The FDA role, of course, again is to approve drug products and assure
> safety and effectiveness, as Dr. Galson described. The primary method
> for the Agency to communicate information to prescribers and
> dispensers is the drug label.
>
> The FDA is also responsible for postmarketing safety and
> phamacovigilance. It is very important to note that the Food, Drug,
> and Cosmetics Act does not distinguish between controlled and other
> drug products.
>
> \[Slide.\]
>
> The State\'s role is primarily achieved through boards of pharmacy and
> medicine, that is, they are the primary regulators of physicians and
> pharmacy practice.
>
> States may impose additional drug controls beyond that of the CSA.
> Authority, regulations, practices, and resources, however, vary
> enormously across states.
>
> \[Slide.\]
>
> Prescription drug monitoring programs have been introduced over the
> past 15 years or so as a regulatory tool for the states. They are
> under the purview of the states, there is no national program, and
> their goal is to reduce illicit use of prescription drugs through
> deterring and identifying so-called doctor shopping, that is, when
> patients obtain medications from multiple physicians simultaneously,
> illicit sales of prescriptions and drugs, and forged prescriptions.
>
> Prescription drug monitoring programs\--and I should note the members
> of the Advisory Committee did have the General Accounting Office
> report on PDMPs included in your background materials\--these programs
> collect, review, and analyze prescription data from pharmacies.
>
> These programs have varied structures, very varied resources. In 2001,
> there were 15 states that had active PDMPs. I believe one additional
> state has come on line in 2003. They vary whether they are electronic
> or paper, whether it\'s a database that can be queried or whether
> there is more active ongoing surveillance.
>
> \[Slide.\]
>
> Again, this schematic just to remind us of the parties that have a
> role in the regulation of controlled substances, and again that the
> patients and the community are mostly out of the regulatory loop.
>
> \[Slide.\]
>
> So, where do we stand on the issues of risk management, drug
> scheduling, and the CSA? I think we can see that scheduling under the
> Controlled Substances Act does not manage all the risks of misuse,
> abuse, and overdose of prescription drugs.
>
> Drug scheduling alone cannot address all the challenges posed by the
> high-dose, extended-release opioid analgesics in the context of the
> modern healthcare system, and it is important to remember again that
> Schedule II designation does not distinguish between high-dose, high-
> potency opioids and low-dose, immediate-release Schedule II drugs.
>
> Thank you, and I guess I also have an opportunity for some questions.
>
> DR. KATZ: Any questions?
>
> \[No response.\]
>
> DR. KATZ: Thank you very much.
>
> I would now like to introduce Terrance Woodworth from the Drug
> Enforcement Administration, who will be speaking with us about the
> DEA\'s Role in the Risk Management of Opioid Analgesics.
>
> **FDA\'s Role in the Risk Management of**
>
> **Opiate Analgesics**
>
> MR. WOODWORTH: Well, it is much too early for this slide. Good
> morning.
>
> Thank you very much for the opportunity to express some of the views
> of the Drug Enforcement Administration concerning the legal framework
> that DEA and FDA operate under together in order to fulfill our
> mandate to protect the public health and safety.
>
> Although very beneficial in the treatment of pain, recently approved
> potent high-dose, extended-release opioids, coupled with aggressive
> and persuasive marketing practices, have brought new and unique
> challenges to our agencies.
>
> Dating back to the passages of the Federal Food, Drug and Cosmetic Act
> in 1906, the United States Congress recognized the critical importance
> of indicating the proven uses of prescription drugs for legitimate
> medical needs. It signaled its full recognition of the abuse potential
> of certain prescription drugs in 1914, when it passed the Harrison
> Narcotic Act regulating the sale of opiates for the first time.
>
> Additional drug legislation over the years including the Controlled
> Substances Act has become part of Title 21, Food and Drugs. With this,
> Congress has indicated its full expectation of a cooperative,
> coordinated interagency process of reviewing a substance and its drug
> products, assessing that drug\'s safety and efficacy, and identifying
> whether it has an abuse potential before permitting its marketing to
> the public.
>
> FDA and DEA have collaborated extremely well in this regard for more
> than 30 years.
>
> It is important to note that there are significant differences between
> the Controlled Substances Act and the Food and Drug Cosmetic Act with
> regard to drugs. One of the most fundamental is that the CSA and its
> controls focus on substances, morphine, oxycodone, where the FDCA
> focuses on products, MS-Contin, Percodan, Adderall.
>
> The Controlled Substances Act places all substances with abuse
> potential into one of five schedules based on accepted medical use,
> potential for abuse, safety, or dependence liability.
>
> Schedule I is for those with no accepted medical use, such as heroin.
> Substances with accepted medical use are in Schedules II through V, II
> being the most restrictive, V being the least restrictive.
>
> When a substance is already in Schedule II of the Controlled
> Substances Act, and Schedule II controls are not sufficient, we must
> look outside the Controlled Substances Act for additional mechanisms
> to prevent diversion and abuse.
>
> The substances that we are addressing today and tomorrow are all
> Schedule II substances under the Controlled Substances Act, thus,
> there are no opportunities for increased levels of control under the
> CSA.
>
> The FDCA, on the other hand, can address product (or class of product)
> safety needs on a product-by-product basis.
>
> In all candor, DEA has not been able to address all of the criminal
> activity associated with high-dose, extended-release opioids in recent
> years. Compounding this difficulty are the indications that FDA\'s
> risk management plan for at least one extended-release opioid has not
> proven effective.
>
> Segments of the pharmaceutical industry in certain cases have exceeded
> traditional drug promotion boundaries and been a significant factor in
> the increased abuse and diversion. State medical boards are unable to
> regulate the increasing numbers of dated, duped, disabled, and
> dishonest practitioners, and physicians themselves acknowledge a need
> for further information and education concerning pain management and
> the use of opioids.
>
> The CSA includes seven major control mechanisms: scheduling,
> registration, quotas, records and reports, import and export
> authorizations, security, and investigational authority.
>
> DEA essentially controls the drug and its movement. We register all
> persons who handle opioids, we inspect the documentation of opioid
> distribution, we control and import and export. We control the amount
> produced, bought, sold, or otherwise transferred.
>
> One would think with all these controls in the so-called closed system
> of distribution that there would be minimal risk of abuse and
> diversion. These controls have been extremely effective in preventing
> diversion at the import or manufacturer and distributor levels,
> however, the vast majority of diversion occurs at the retail level
> once the product is in the hands of practitioners and patients.
>
> Significant weaknesses in two of the controls, quotas and
> investigational authority have contributed to the increases in abuse
> and diversion.
>
> With regard to investigational authority, it is estimated that more
> than 90 percent of the diversion occurs at the doctor/pharmacy level,
> however, at this retail level, it is primarily the states and the
> professional boards responsibility, not DEA, to regulate and oversee
> controlled substances activities. DEA is not directly involved in the
> establishment of medical or pharmacy standards, nor are we directly
> involved in the regulation or investigation of medical or pharmacy
> practice.
>
> DEA investigates physicians who are acting outside the norms of
> accepted medical practice, thus, the responsibility at the retail
> level for controlled substances rests, in general, with a wide array
> of different state and medical and pharmacy boards.
>
> \[Break due to power failure.\]
>
> DR. KATZ: Our break seems to be finished, so we will continue.
>
> Mr. Woodworth.
>
> MR. WOODWORTH: Well, a lot of people have said DEA is in the dark on
> these issues, but that is a little bit much.
>
> \[Laughter.\]
>
> MR. WOODWORTH: In evaluating a physician\'s or a pharmacist\'s
> activities relating to the management of pain and the use of opioids,
> the state boards rely heavily on the FDA approved labeling for
> opioids, as do physicians themselves.
>
> FDA-approved labeling provides guidance to the medical community
> regarding conditions for safe use, as well as providing safety and
> other warnings. Labeling and risk management plans have a direct
> impact on the extent of abuse and diversion of opioids, but DEA has no
> statutory authority to participate in the development of the labeling
> or risk management plans except for our role in scheduling, as Dr.
> Leiderman mentioned.
>
> At present, under Section 201(f), when HHS receives a New Drug
> Application for a stimulant, depressant, or hallucinogenic drug, and
> the drug appears to have an abuse potential, HHS is required to
> forward that information to DEA for scheduling purposes. For
> substances already in Schedule II, DEA has no authority to require
> additional controls.
>
> The key to having the ability to further deter and prevent abuse and
> diversion becomes the labeling of new formulations of already
> controlled substances. When FDA-approved labeling indicates that
> extended-release forms of opioids may have less abuse liability, as
> was the case with OxyContin, this significantly affects decisions of
> physicians to prescribe a drug, as well as the medical board\'s action
> in reviewing a physician\'s activities.
>
> With regard to quotas, DEA and FDA are responsible for ensuring an
> adequate and uninterrupted supply of opioids for medical, scientific,
> and research needs of the United States. We accomplished this by
> establishing quotas for the total quantity of each basic class of
> controlled substances, oxycodone, for example, which may be
> manufactured in the United States on an annual basis.
>
> The purpose of the quota system is to limit the availability of
> legitimately manufactured controlled substances which may be diverted
> into the illicit market. Increased availability and access to
> controlled substances are direct causes of abuse and diversion.
>
> Quotas are established considering sales from the previous year,
> estimates of year-end inventory, and estimates of legitimate medical
> needs in the future provided to DEA by FDA.
>
> On the surface, the quota system appears to be an effective means of
> limiting the supply of opioids to what is legitimately needed for
> medicine and science in this country. After all, the drugs have been
> approved for safety and efficacy, and the pharmaceutical manufacturers
> have been through a rigorous FDA and DEA approval process.
>
> However, both DEA and FDA are receiving the using incomplete
> information regarding what actually are the legitimate medical needs
> for opioids in this country. Again, legitimate medical need is largely
> determined by sales.
>
> Sales are prescriptions, all prescriptions for extended-release,
> high-dose opioids are counted in the total sales figures to establish
> quotas regardless of whether those prescriptions were illegal,
> indiscriminate, or inappropriate.
>
> How can the estimates of legitimate medical needs for
> extended-release, high-dose opioids be based on totals that include
> illegitimate sales, and what is the volume of those illegitimate
> sales?
>
> Quotas can help limit the amount of substance that can be manufactured
> in a year, but quotas, nor any other control mechanism, can ensure
> that correct amounts of medicine get to the correct people for the
> correct indications.
>
> It is reasonable to expect that increasing availability of most, if
> not all, Schedule II opioids will be associated with a commensurate
> increase in diversion and abuse.
>
> Finally, we get to the slides.
>
> \[Slide.\]
>
> Data available to DEA - aggregate production quotas, year-end reports,
> or distribution data to the retail level and IMS retail provider
> perspective, which are purchases at the retail level - show a
> consistent increase in availability for morphine, hydrocodone, and
> oxycodone over at least the past eight years.
>
> \[Slide.\]
>
> When availability data, as measured by total prescriptions, is
> compared to Drug Abuse Warning Network emergency department episodes
> for the same substances, it appears there is not only an increasing
> abuse, but increasing rates of abuse. This is particularly true for
> oxycodone since the introduction of OxyContin.
>
> There are several factors that we believe have contributed to the
> incomplete and unreliable information that DEA and FDA are using as a
> basis for prescribing and ultimately determining legitimate medical
> need.
>
> These factors have led to increased availability and that has made
> diversion easier and abuse more prevalent.
>
> First, the initial labeling for OxyContin allowed great latitude for
> prescribing, promotion and marketing of this substance.
>
> It is indicated, as you know, for moderate to severe pain. This
> allowed for the promotion of the product as a substitute for products
> such as Tylenol with codeine, Darvocet, Vicodin, and other Schedule
> III and IV products.
>
> The labeled indications also allowed for considerable interpretation
> regarding its use in acute versus chronic pain, postoperative pain,
> and other situations. It also supported promotion to all types of
> practitioners, particularly family practitioners and internists, not
> all of whom are appropriately trained in pain management and the use
> of these relatively new and unique products.
>
> It was not described as a \"potent\" opioid analgesic as was morphine
> in the MS Contin labeling. This and other parts of the labeling did
> not convey the message that OxyContin was to be treated as cautiously
> as MS Contin.
>
> In describing the dependence, the term \"psychological dependence\"
> was omitted for OxyContin, but not for MS Contin.
>
> The labeling also stated that controlled-release opioids were believed
> to have less abuse liability.
>
> Second, unusually aggressive and persuasive marketing and promotion
> techniques used by manufacturers and their sales personnel.
>
> DEA has obtained and evaluated data on the promotion of six high-dose,
> controlled-release, Schedule II narcotic analgesics presently marketed
> in the United States - OxyContin, Duragesic, MS Contin, Kadian,
> Oramorph, and Avinza.
>
> The data shows that there is a positive correlation between the amount
> of money spent on promotional activities and the amount of sales and
> prescriptions. Those companies spending the most money generally have
> the most sales.
>
> By far, more money has been spent on the promotion of OxyContin, as
> you can see in this slide, than the other products combined. There is
> nothing wrong with promoting a drug product in the proper context.
> Unfortunately, we believe that the initial labeling allowed this
> product to be promoted for too large a range of conditions, to those
> physicians not adequately trained in pain management, and without the
> proper warnings about its abuse potential.
>
> The data reviewed show the scope of medical specialty groups was
> widest for OxyContin. There was less emphasis on promoting to
> \"traditional\" pain specialty groups.
>
> For example, in 2000, anesthesiologists received the most promotion
> dollars for Actiq, Avinza, Kadian, and MS Contin. Promotion for
> Duragesic was highest for internal medicine, with anesthesiologists
> second.
>
> In the case of OxyContin, family practitioners and internists were in
> first and second positions respectively. In addition, more money was
> spent promoting OxyContin to nurse practitioners, physician
> assistants, and general practice doctors than the entire promotional
> dollars spent on Kadian, Oramorph, or Avinza. Unfortunately, these
> medical groups are not pain specialists.
>
> Finally, we examined the message given to these medical groups. IMS
> Message Insight monitors the messages being conveyed to physicians and
> actually provides summaries of the physicians\' impressions of the
> sales contact.
>
> Here, there are subtle differences, but significant, between OxyContin
> and Duragesic. No data was available for the other high-dose products
> except very limited comments for MS Contin.
>
> The primary message that physicians received regarding Duragesic was
> that it should be used for chronic pain management. The few mentions
> for MS Contin also indicated that it was being promoted for chronic
> pain treatment. Physicians heard a far different message regarding the
> appropriate use for OxyContin.
>
> These factors present serious obstacles to both DEA and FDA in our
> attempts to determine legitimate medical need, establish appropriate
> quotas, and conduct successful investigations. The result is our lack
> of success in preventing abuse and diversion of extended-release,
> high-dose opioids.
>
> We have found that where companies have instituted voluntary risk
> management plans, and in those situations in which FDA has required
> them, the results have been encouraging in preventing the excess
> availability, diversion, and abuse of these products.
>
> We are also aware that the labeling for OxyContin has been changed to
> address some of the above concerns. Our question is would it not be
> more effective, considering the severe potential for abuse, diversion,
> physical and psychological dependence posed by these
> never-before-produced, high-dose, extended-release opioids, to start a
> little slower and more cautiously with a greater regard for patients?
>
> It is far more reasonable to focus on patients whose needs for these
> drugs are already unquestioned by healthcare, regulatory, and law
> enforcement authorities.
>
> In conclusion, what does DEA think will help? DEA believes that a
> mandatory risk management plan for these high-dose, extended-release
> products should include:
>
> Some form of restriction on the distribution and/or dispensing of
> these products;
>
> Secondly, limit the indications to severe pain or certain disease
> states, or only in certain situations where other Schedule II opiates
> have failed;
>
> Three, review and approve all promotional material in advance;
>
> Prominent warnings, such as the current Black Box on Actiq and
> OxyContin;
>
> Postmarketing surveillance for monitoring the adverse events,
> diversion, and abuse for several years;
>
> Physician, pharmacist, and patient education regarding the proper use
> and adverse effects of potent, high-dose, extended-release opioids.
>
> DEA and FDA have worked extremely closely for decades on all
> controlled substances issues, but we are continuing to do so at a much
> closer and active pace with regard to extended-release, high-dose
> opioids.
>
> We are collaborating on many issues including, as Dr. Leiderman
> mentioned, physician education, prescription monitoring programs, as
> well as in the area of risk management as far as DEA is able to go.
>
> Our goal, together, at DEA and FDA, is to limit the diversion and
> abuse of opioids and at the same time ensure that the American public
> has an adequate and uninterrupted supply of opioids for legitimate
> medical needs.
>
> We do feel that we should limit the production, distribution, and
> access, promotion, and, of course, the labeling for these high-dose,
> extended-release opioids, and we should only gradually expand patient
> access as our system of standards and controls prove capable of
> providing for the appropriate treatment of patients by knowledgeable
> practitioners for accepted medical purposes.
>
> We should not unlock the safeguards until we can adequately defend
> against abuse and diversion. The undertreatment of pain in this
> country and throughout the world is not a valid reason to wantonly
> increase production, availability, access to this select group of
> drugs that can significantly harm the public health and safety.
>
> Government approval of a drug does not guarantee its safe use, you
> heard that earlier. When a potent, government-approved drug is
> aggressively promoted with incorrect messages about its use and
> indications and its legitimate medical need, it becomes an unsafe
> drug.
>
> The result of such action by a drug manufacturer, further aggravated
> by the drug\'s deliberate misuse and abuse in the illicit market, is a
> serious issue bearing on the American public health and safety.
>
> With that, I see my yellow light is on and I will take any questions
> you may have.
>
> DR. KATZ: Thank you, Mr. Woodworth.
>
> Are there any questions from around the table for Mr. Woodworth? Bob.
>
> DR. DWORKIN: Yes. You had mentioned that 90 percent of the diversion
> occurs from the pharmacy onwards in the supply chain.
>
> Does the DEA have any data about what percent of that 90 percent
> occurs at the level of the pharmacy and what percent of the diversion
> occurs after a valid prescription has been filled, because those are
> two very different contacts, of course?
>
> MR. WOODWORTH: That is an excellent question and extremely difficult
> conclusion to draw. What we have been able to do with the American
> Medical Association over the years is estimate, with regard to
> physicians, that 1 1/2 to 2 percent of physicians are dishonest, and
> another 5 percent are negligent.
>
> So, then you are talking about 7 percent of the physicians. There
> about a million physicians registered with DEA in the United States.
> So, while that is an extremely low percentage, meaning that most
> doctors are good, law-abiding physicians, 7 percent of a million is
> 70,000, 70,000 physicians can account for a lot of illegal
> prescriptions and millions of dosage units.
>
> With regard to diversion at the pharmacy level, most of DEA\'s
> activities have been as the result of criminal investigations, and the
> cases we make on pharmacies are usually associated with a physician\'s
> activities.
>
> So, frequently, if there is a bad doctor in a town, there is one or
> two or three pharmacies that are not adhering to their corresponding
> responsibility to ensure that that prescription is issued for a
> legitimate medical need.
>
> So, in order to shortly answer your question, I think the answer is
> there is more doctors that we have had situations interact with than
> pharmacies, and certainly there is a larger number of doctors than
> there are pharmacies. It is about 60,000 pharmacies in the United
> States.
>
> DR. KATZ: Dr. Shafer.
>
> DR. SHAFER: Thank you. A couple of questions, but the main one is,
> looking at your slides, you have equated DAWN emergency department
> mentions assays surrogate for drug abuse.
>
> Certainly in the excellent package that we were provided prior to this
> meeting, there is quite a bit of discussion about the DAWN database,
> but it wasn\'t clear from anything that I saw in that packet that
> emergency department mentions in the DAWN database was actually a
> surrogate for abuse.
>
> Can you comment on that, please?
>
> MR. WOODWORTH: It is clearly an indicator. We feel comfortable using
> DAWN, not only because of its history of use, the use of emergency
> department mentions as an indicator of abuse, but it corresponds with
> all of the other data that DEA has, our federal investigations, our
> investigations of our state and local counterparts.
>
> I have just thrown up a slide of our state and local seizures. This is
> called the National Forensic Laboratory Information System. There is
> about 300 forensic labs in the United States. They submit data to a
> database and it is collated.
>
> As you can see, in red, is oxycodone, and in kind of a yellowish is
> hydrocodone. Those two substances account for more than 70 percent in
> the last three years of all of the state and local law enforcement
> forensically analyzed exhibits, which is again a strong indication of
> what law enforcement is encountering on the street.
>
> They are all indicators that are used together, so I feel comfortable
> drawing that conclusion.
>
> DR. KATZ: I believe Dr. Strom was next.
>
> DR. STROM: Thanks. Can you share with us, do you have a sense of what
> proportion of prescription opiates get diverted and, conversely, what
> proportion of illicit drug use comes from diverted prescriptions?
>
> I am trying to get a sense of how big is the diversion problem
> relative to other sources of abused drugs.
>
> MR. WOODWORTH: I am unable to quote precise statistics, but if you
> look at all of the accepted indicators, in addition to the DAWN
> emergency department mentions, the now National Household Survey,
> again, our National Forensic Laboratory Information System, other
> surveys and studies, the indications are that prescription drug abuse
> has been increasing for the last decade or so, and the abuse and
> diversion of prescription opioids has increased at a greater rate.
>
> DR. KATZ: Because of scheduling issues, we are going to have to
> curtail the discussion now. We will have time to interact with our DEA
> colleagues and also hear more material presented from them later in
> the day.
>
> Let me thank Mr. Woodworth for coming by and hopefully, they will
> stick around for more questions later.
>
> We are having a slight detour in our schedule now which I would like
> to describe for you. We are actually scheduled for a break, but we are
> not going to do that. As I mentioned earlier, we would have a number
> of open public hearings during the two days of our meeting, and we are
> going to have a portion of our open public hearing now because two
> representatives from Congress are here to share some thoughts with us
> about this issue.
>
> So, this is part of the open public hearing and, as such, I am
> required to read the following statement by the FDA, which I will read
> before this section of the open public hearing and later in the
> afternoon when we have an open public hearing and tomorrow when we
> have the same thing. So this is the general statement about financial
> disclosure and conflict of interest.
>
> Both the Food and Drug Administration and the public believe in a
> transparent process for information gathering and decisionmaking. To
> ensure such transparency at the open public hearing session of the
> Advisory Committee meeting, FDA believes that it is important to
> understand the context of an individual\'s presentation.
>
> For this reason, FDA encourages you, the open public hearing speaker,
> at the beginning of your written or oral statement, to advise the
> committee of any financial relationship that you may have with any
> company or any group that is likely to be impacted by the topic of
> this meeting. For example, the financial information may include a
> company\'s or a group\'s payment of your travel, lodging, or other
> expenses in connection with your attendance at the meeting.
>
> Likewise, FDA encourages you, at the beginning of your statement, to
> advise the committee if you do not have any such financial
> relationships. If you choose not to address this issue of financial
> relationships at the beginning of your statement, it will not preclude
> you from speaking.
>
> So, once again, that is a general statement that I will read before
> all of the open public hearings.
>
> **Open Public Hearing**
>
> DR. KATZ: Now, it is my privilege to introduce Congressman Harold
> Rogers, who will be sharing some thoughts with us about risk
> management programs for opioid analgesics.
>
> Congressman Rogers.
>
> MR. ROGERS: Thank you, Mr. Chairman.
>
> I have no financial interest. The only interest I have is that we have
> a lot of young people who are dying in my district because of
> addiction to OxyContin.
>
> This is truly a life and death question that the Advisory Committee is
> undertaking here. I want to tell you about a couple of those types of
> cases that I have endured in my part of Kentucky.
>
> Before I do that, however, Frank Wolf, Congressman Wolf and I were
> just chatting. Perhaps you can help me. I am trying to think of the
> mythological figure, the captain of the ship that was so enticed and
> excited by the sirens on short\--who is it? Ulysses. You get an A.
>
> He was so excited that he had his crew strap him to the mast of the
> ship as they sailed past the place where the sirens, the beautiful
> women on shore were enticing him. It reminds me a little bit of the
> enticement of this wonderful drug OxyContin, which has meant so much
> to people in severe pain, that has been abused by users, by doctors,
> by companies, by pharmacies to the point that we are toying with a
> severe problem.
>
> Frankly, this is the most devastating thing that I have seen in my
> more than 22 years now in the U.S. Congress, in my district. I have
> never seen anything like this. This drug is tearing apart families, it
> is ruining lives, it is stretching the resources of law enforcement
> and social service agencies to the absolute limit, and it has actually
> reached epidemic proportions in my district, which is southeast
> Kentucky.
>
> In fact, we have become the prescription painkiller capital of the
> United States. An analysis of federal drug data found that on a per
> capita basis, our drugstores, hospitals, and other legal outlets
> receive more prescription painkillers than anywhere else in the
> nation.
>
> From 1998 to 2001, nearly half a ton of narcotics reached seven small
> mountain counties. That is the equivalent of more than 3,000
> milligrams for every adult who lives there. A typical pill might
> contain 10 to 20 milligrams.
>
> A lot of this medication obviously is for legitimate purposes, too
> much of it is not. These drugs are hitting the streets, they are
> leading to addiction, crime, death. A public defender in one of my
> countries, Perry County, a small mountain county in my district, this
> public defender estimated that 95 percent of his clients either sell
> or abuse prescription drugs.
>
> Because of this epidemic, our courts are unable to keep up with this
> overwhelming pace of new crimes. An eastern Kentucky court, the court
> dockets are jammed with these drugs cases. In recent years, charges
> for controlled substances have jumped 348 percent.
>
> Our residential drug treatment centers are overwhelmed, admissions
> tripling since 1998. A Prestonsburg, Kentucky drug treatment program
> director reports that the new patients, most of whom are hooked on
> OxyContin, are younger and sicker than ever, and they are dying.
>
> Nationwide, according to the statistics, OxyContin played a major role
> in 464 overdose deaths in the nation between May of 2000 and February
> of 2002. A quarter of these occurred in Kentucky and Virginia alone,
> and most of them were young people who were not in severe pain when
> they first were prescribed this medicine.
>
> Thus, the question, should we restrict the use of this wonderful drug
> to those in severe pain or just moderate pain, a toe ache, a
> toothache, a broken arm? Ulysses.
>
> Let me tell you about two of these people, thus, my motivation.
> Congressman Wolf is the Chairman of the Commerce Justice State
> Subcommittee on Appropriations, the committee that I formerly was
> chairman of.
>
> Our two states have been impacted severely by this problem, and we
> first were attracted to the problem a couple or three years ago, and
> had a hearing. I bought up to that hearing from my district, a
> preacher whose son had become addicted to OxyContin, and the preacher
> testified, and he had his son with him, who was at the time I think 21
> or so.
>
> The son never testified. He sat beside his father while his father
> described I think it was an automobile accident he had been in, the
> young man, and had been prescribed OxyContin and became absolutely,
> hopelessly addicted. He would do anything to get the drug - steal,
> cheat, lie, to name just a few.
>
> The father was absolutely devastated obviously by the predicament of
> his son. Finally, he was able to find in Indiana, I think it was, a
> church-affiliated or church-related treatment center that was able
> finally to take the son in, in an attempt to defeat this addiction.
>
> This was the substance of the testimony of Reverend Coots before the
> Subcommittee, the son sitting beside him, I will never forget the
> sight, because two or three months later, the young man overdosed and
> died.
>
> Now, the father, the preacher heads up a group that he formed himself
> called Joshua\'s Promise. Joshua was his son\'s name. Now, he raises
> money and takes in people like Joshua into this center there in the
> mountains to try to help them defeat this insidious addiction.
>
> The other death I want to tell you about is of a close personal friend
> of mine who happened to have been the sheriff of my home county,
> Pulaski County. He was assassinated by a crazed young man hiding in
> the forest adjacent to a political picnic the sheriff had attended
> with a sniper rifle, one shot, instant death.
>
> It turns out the shooter was on OxyContin at the time. He was
> affiliated with a man who was running for sheriff, against the
> sheriff, in a political race, all of it financed, that man\'s campaign
> financed by a drug dealer.
>
> I had the duty to speak at the funeral of Sheriff Sam Catrin, personal
> friend, wonderful public servant, sheriff I think 17 years, named
> Sheriff of the Year, a tremendous law enforcement officer whose life
> and career snuffed out by a OxyContin-addicted, crazed killer.
>
> So, I say to the committee I don\'t envy you your responsibility. This
> is a tough one. We want to believe that our pharmaceutical
> manufacturers do the right thing all the time. There is a real
> question here about the practices of overselling, overpromoting the
> use of OxyContin to doctors, to pharmacies, to the public because this
> drug is so enticing and so alluring that I think you must tie us to
> the mast as we pass by this very alluring drug and restrict its use to
> the most severe cases, not to the broken fingers, because it is so
> addictive, so addictive and so devastating that we are killing our
> young people.
>
> OxyContin has been overly aggressively marketed especially to rural
> physicians, physicians who don\'t have that much experience with
> severe pain and the way pain medications should be prescribed.
>
> Two, OxyContin is defined as being for moderate pain, and for that
> reason, it has become too easily prescribed, too easily available
> especially to young people who crush that 12-hour time release
> mechanism to get the instant release.
>
> Reverend Coots told our subcommittee that his son told him that this
> drug was so wonderful and the reason it was so addictive and so
> pleasurable to the young man, he said it felt like a constant orgasm.
> Thus, you can see the appeal of this drug to especially young people.
>
> Let me give you a few examples of what corrupt doctors are doing in
> Kentucky. This past September, a year ago, a doctor was arrested,
> federal authorities, overprescribing. He had prescribed on average 800
> prescriptions a month.
>
> What is most appalling in this case is that the doctor actually
> expressed concern to his colleagues about the amount of OxyContin he
> was prescribing. Who else did he express his concern to? His Purdue
> Pharma sales rep, who told the doctor then, who happened to be a very
> top client of his, the sales rep reassured him that he was doing the
> right thing.
>
> Another doctor in Kentucky prescribed more than 2.3 million pills to
> more than 4,000 patients over 101 days. Did you hear me? 2.3 million
> pills to 4,000 patients over 100 days. It\'s a drive-through
> prescription service.
>
> Another doctor in Harlan County, Kentucky, who is now serving 20 years
> on a federal drug conviction, saw 133 patients in a day, in an office
> without electricity. He has been prescribing OxyContin and Viagra to
> teenage boys.
>
> Now, we will take care of those doctors, we will take care of them,
> don\'t you worry. DEA, the other law enforcement agencies, local
> sheriffs, police are overwhelmed, but they are getting to them. That
> is not the real problem.
>
> We have even started in my district a program we call UNITE, Unlawful
> Narcotics, Investigations, Treatment, and Education. We are mobilizing
> the whole population to fight this insidious problem. And you know
> what? People are really excited about it.
>
> We are going to bring in 30 new undercover agents, the U.S. Attorney,
> the local prosecutors are all plugged in. The State Supreme Court is
> now setting up drug courts in every one of my 29 counties as a part of
> UNITE.
>
> We are trying to mobilize all of the treatment centers to try to give
> them new ammunition, new monies, new possibilities, some coordination,
> but they are overwhelmed. The State has its prescription monitoring
> program called KASPER.
>
> Congressman Wolf inserted money in his appropriations bill for the
> Justice Department over the last two, three years, monies to help
> states like Kentucky start prescription monitoring programs and
> modernize them as we go. Those monies are being used, but that is not
> enough.
>
> So long as the FDA allows doctors and endorses the practice of
> prescribing this insidious but alluring addictive drug for a broken
> finger, we will have this problem.
>
> We cannot fight it on that end. It has got to be fought at the source.
> The flood is too great for us to deal with down there. It has got to
> be dealt with where the huge amounts of these drugs are being allowed
> to flow.
>
> You must restrict, tie us to the mast, restrict the use of this
> insidious, alluring drug to severe pain and no more before it\'s too
> late. This is a wonderful drug for people who need it. I don\'t want
> it said that I don\'t want people in severe pain to have access to
> this wonderful released drug for severe and debilitating pain, but its
> use has gotten out of hand.
>
> It is causing death and destruction and families are being rendered
> and torn apart. It is not just in rural Kentucky now, it has spread
> across the country, and unless you stop this now, it will cause many
> more deaths and renderings of parts of families.
>
> I want to leave with you, Mr. Chairman, a packet of materials. These
> are photocopies of the stories that ran in the Lexington, Kentucky
> newspaper, two different series, that were absolutely accurate, as
> well as devastating in their investigations into the problem in our
> state.
>
> If you read these stories, you will have no doubt. This will solve
> your perplexing question. It is absolutely devastating especially the
> last series that detailed how this company oversold this product, the
> sales reps even telling the doctor, in his notes after meeting with
> the doctor, saying to the effect we must push these pills more.
>
> I will leave this with you. Thank you.
>
> DR. KATZ: Thank you, Congressman Rogers for taking time to share your
> experiences with us. I can assure you that we appreciate the serious
> nature of the problems you are describing and we will be struggling
> with them over the next couple of days.
>
> I would now like to introduce Congressman Frank Wolf, who will also
> share his thoughts and experience in this issue with us.
>
> MR. WOLF: Thank you very much and I will be very, very brief.
>
> One, I want to thank you and thank the Food and Drug Administration
> for conducting this important review, and I share the comments of my
> colleague, Mr. Rogers, on pain management drugs.
>
> Let me begin by also emphasizing that I am not here seeking to remove
> OxyContin from the market. When used correctly, OxyContin serves an
> important purpose in assisting those with excruciating chronic pain or
> those who are terminally ill. Both my mom and dad died of cancer. My
> mom particularly suffered. I remember at the Hahnemann Hospital, the
> doctor would just say we have given your mom four hours ago and we
> can\'t do it again, so I understand and I want to make it clear that I
> am not trying to take this drug away from people like that.
>
> However, I believe that the Food and Drug Administration and the
> Department of Health Services have been slow to respond to the growing
> problem related to drugs, such as OxyContin, which have a darker side
> and can be highly addictive.
>
> I am concerned that the powerful painkiller has increased and become a
> drug of choice for people who choose to abuse these drugs, for people
> who have no legitimate need for the painkilling drug.
>
> FDA, I noticed, and you remember, moved quickly to address the
> problems with the dietary supplement Ephedra when a professional
> baseball player died during spring training this year. Where is the
> same urgency with OxyContin?
>
> OxyContin\'s producer, Purdue Pharma, has spent huge sums of hiring
> lobbyists, slick high-paid lobbyists that are well connected to
> powerful people in Washington, lawyers, lobbyists, and spin doctors
> for a public relations and marketing campaign to defend themselves and
> their products.
>
> But who represents the poor and the suffering and the Joshuas and the
> people like that who can\'t hire the big firms from New York and
> Washington to come in and have direct access to the prominent people
> who make decisions in this town?
>
> I believe that some of that PR money could have been better spent
> finding ways to stop OxyContin abuse and save lives. OxyContin is
> leaving a trail of broken lives, murder, suicide, grieving families,
> and growing law enforcement problems.
>
> Kentucky, Tennessee, West Virginia, and now my home state of Virginia
> have seen a spike in the reports of OxyContin. Down in Lee County in
> southwest Virginia, there is almost not a family that has not been
> impacted, either someone is using it, somebody has been robbed by it,
> somebody has been arrested, that has not been impacted at all because
> of OxyContin.
>
> In northern Virginia, in my congressional district, federal officials
> have now launched what they call Operation Cotton Candy, which has
> targeted between 60 and 80 people, who are believed to be involved in
> the illegal distribution of OxyContin.
>
> Prosecutors claim that the amount of OxyContin improperly prescribed
> by this network of dealers is obscene. You probably have read the
> story in West Virginia, a mother was charged with trying to sell her
> young son, a mother, the relationship with the young son trying to
> sell a young son for \$500, so she could buy OxyContin.
>
> Federal officials have said that no other drug in the last 20 years
> has been so abused in such a short period of time. More than a
> hundred, several hundreds, 2-, 3-, 4-, now some say up to 500 people
> have died due to OxyContin.
>
> Lives have been destroyed, and again Ephedra, they moved quickly.
> Big-time ballplayer, everybody knows his name, they moved. The
> Joshuas, they do absolutely nothing for, and I remember that hearing.
> The young boy had an electric blue suitcoat on, a little bit out of
> style, but his dad was so proud that he was there because he had gone
> through this rehab program, and he thought he was cured, and then as
> Hal said, several months later the boy overdosed.
>
> The FDA, and I believe all of you, and I appreciate your service here,
> we have a responsibility to do much more to look at why OxyContin is
> being abused, why is it being abused, how is it prescribed, what
> levels of pain require a drug such as OxyContin, what steps must be
> taken to halt the abuse of these drugs, so that people can stop dying.
>
> Again, I want to thank all of you for taking the time. I also want to
> thank the Commission, the Food and Drug Administration for convening
> this. We stand ready, whatever recommendations you make to try to help
> you, but what you do today and what you do based on this hearing,
> literally will be the difference of how many more Joshuas and how many
> more Marys and how many more families are destroyed, and I thank you
> very much for what you are going to be doing.
>
> DR. KATZ: Thank you, Congressman Wolf, for sharing your thoughts with
> us.
>
> We will take a 15-minute break.
>
> \[Break.\]
>
> DR. KATZ: It is a pleasure for me to introduce our next speaker Dr.
> Art Lipman. Dr. Lipman is going to be particularly valuable for us
> today since he has been steeped in the development of pain management
> guidelines including guidelines surrounding opioid use for many
> decades and, in particular, has been a leader in taking an
> evidence-based approach to guideline development.
>
> He has been involved with the AHCPR panels and acute and cancer pain,
> has been a co-chair of the American Pain Society Panel on Arthritis
> Pain Management that produced guidelines, is on the Clinical Practice
> Guidelines Committee at APS, and Dr. Lipman will be speaking with us
> about the risk:benefit relationship of opioids, and then Steve Passik,
> in a subsequent session, will be talking about the addiction piece of
> that risk:benefit equation.
>
> Dr. Lipman, please.
>
> **Opioid Risk:Benefit Contradiction**
>
> DR. LIPMAN: Thank you, Mr. Chairman, and my thanks to the Committee
> and to the Division for inviting me to come and present information
> today.
>
> As Nat mentioned, my interest is the evidence-based aspect, and I
> speak as an editor on the Cochrane Collaboration, which as most of you
> know, is the international collaboration based at Oxford University on
> evidence-based medicine, and we have a specific pain, palliative, and
> supportive care group here that looks extensively at the issue of
> opioids in an evidence-based manner.
>
> \[Slide.\]
>
> Let me just set the stage by this quote from two of the leading pain
> researchers of the world a number of years ago, the late Dr. John
> Liebeskind of UCLA, and Dr. Ron Melzack of McGill, who said they were
> \"appalled by the needless pain, freedom from pain should be a basic
> human right limited only by our ability to achieve it.\" Now, that was
> written in the year 1987, as you see.
>
> \[Slide.\]
>
> A decade later, this was the cover of U.S. News & World Report, and as
> you see, it reads, \"Doctors have the means at hand to relieve the
> suffering of millions of Americans, why aren\'t they doing it?\"
>
> Then, in small print are the words, \"New science, old thinking.\"
>
> Now, all of us in our professional education and training learn from
> our mentors. Unfortunately, much of what our mentors taught us was not
> necessarily accurate, and as we take an evidence-based approach to
> medicine, we recognize that perhaps we have to refresh some of our
> thinking.
>
> \[Slide.\]
>
> That is the reason that when Congress mandated the writing of clinical
> practice guidelines in the closing days of 1989, that when Secretary
> Sullivan, Dr. Louis Sullivan then Secretary of the Department of
> Health and Human Services had the mandate to create clinical practice
> guidelines, he immediately said he first guideline that he was going
> to develop was in pain because he got more calls from members of
> Congress about pain management than any other health-related problem
> on behalf of their constituents.
>
> Now, this is a very serious issue. When we convened in this city,
> actually, in Washington, D.C. in August of 1990, we recognized that we
> could not address in a single evidence-based document all of the
> issues, but this document that was published in 1992, entitled
> \"Clinical Practice Guideline Acute Pain Management,\" and then
> subsequently, the panel was expanded from 16 to 25 members, this
> document that was published in 1994 laid the basis in the United
> States of America for evidence-based care in the management of pain.
>
> \[Slide.\]
>
> Now, what is important is we didn\'t take anecdote, we didn\'t take
> political perspectives, we didn\'t take individual cases and try to
> generalize them to the population, but we looked at the true quality
> and quantity of the evidence.
>
> \[Slide.\]
>
> As Dr. Katz mentioned, just this past year we published the American
> Pain Society evidence-based guideline on the management of
> osteoarthritis, rheumatoid arthritis, and chronic juvenile arthritis
> pain using the same evidence-based methodology.
>
> I wish I had time to go into that methodology at length, but it has
> been generally accepted by the better people in the field as being
> appropriate.
>
> \[Slide.\]
>
> Of course, the American Pain Society publishes its well-respected
> booklet entitled \"Principles of Analgesic Use in the Treatment of
> Acute Pain and Cancer Pain,\" and what nobody else in this room knows
> now, but I will tell you, is that at the end of this month, the Fifth
> Edition, which we completed last month, will be published by the
> American Pain Society, and it has a lot more information on the use of
> opioids.
>
> Now, what did all this evidence-based work teach us? It taught us that
> opioids are important therapeutic entities, but more importantly, it
> taught us that very few clinicians, and I suspect very few clinicians
> in this, and I speak as a clinician and investigator in pain work for
> the past three decades, very few understand the seriousness of pain
> and why opioids need to be used in an appropriate context.
>
> \[Slide.\]
>
> Indeed, when we convened in Washington in 1990 to be the federal
> panel, we were assigned a team of research librarians from the
> National Library of Medicine just up the street from where we are
> sitting now, and the world literature indicated the adverse outcomes
> of undertreated pain are far more serious than most of us appreciated.
>
> We were all experienced clinicians, we were all experienced
> investigators. Not one of us knew how serious pain is. The single
> biggest issue physiologically is catabolism. We put patients into a
> physiological state where they don\'t heal, they are weak, there is
> muscle breakdown, and they are predisposed to depression.
>
> We see increased throwing of clots, we see adverse respiratory, salt,
> water, renal, cardiovascular effects.
>
> \[Slide.\]
>
> Beyond the physiological adverse outcomes of undertreated pain are the
> adverse psychological outcomes - anxiety, depression, sleep
> deprivation, and the serious question why I am even alive.
>
> \[Slide.\]
>
> Perhaps most interesting, and we presented more data on this at the
> American Pain Society meetings last year, are the adverse
> immunological effects of pain, work that was pioneered in Dr.
> Liebeskind\'s lab showing decreased body host defenses from pain.
>
> Now, what does all this mean? If we are going to advocate for the
> American public, the good congressman said a few minutes ago who is
> going to advocate for Joshua, I raised my hand. I am here to advocate
> for Joshua. My son\'s name is Joshua, it hit home. The issue is we
> have to look at the science, and the science tells that we based
> rational therapy on risk-benefit ratios.
>
> Everyone knows that, but unless we appreciate the risk of undertreated
> pain, we are not going to get adequate therapy.
>
> \[Slide.\]
>
> Some of the elegant work done by Dr. Charles Cleeland and his
> colleagues, Charlie is now at M.D. Anderson, he was at Wisconsin when
> he did this work, and, of course, Dr. Cleeland developed the pain
> inventory with the 1 to 10 scale, well validated, with zero being no
> pain, 10 is as bad as you can imagine.
>
> He actually quantified in a large series of patients the impact on
> their ability to function, functional outcomes, something the Agency
> is very interested in, according to the pain intensity.
>
> Now, 1 to 3 is mild pain, 4 to 7 is moderate pain, 8, 9, and 10 is
> severe pain. Look at the impact. Ability to carry out activity,
> ability to work normally, ability to enjoy life are impaired at level
> 4, activity, mood, ability to work and enjoyment of life at level 5,
> sleep, activity, mood, ability to work, to enjoy life at level 6. That
> is not severe pain, that\'s moderate pain.
>
> Moderate pain is a bigger problem in much of American society than
> severe pain, because anybody in this room who has ever had an aching
> back for two or three days knows how that wears you down emotionally,
> physiologically, you don\'t sleep, and that is mild to moderate pain.
>
> \[Slide.\]
>
> Well, if we are going to look at this from a scientific perspective,
> and look at risk:benefit ratios, we have to recognize that the risk of
> pain is often much greater than the risk of the therapies that we are
> using.
>
> There is an inherent risk in pharmacotherapy. I have always told since
> I started teaching medical students at Yale Medical School in 1971, I
> said look around the room to the third-year students in their first
> clinical pharmacology exposure and said somebody in this room is going
> to kill someone with a drug he or she prescribes, but that doesn\'t
> mean we are not going to use the medications.
>
> Yes, there have been deaths, and, yes, there will continue to be
> deaths. I strongly contest the numbers that came there because I have
> looked at some of the autopsy data and other issues that come out, and
> as I am sure the scientists and clinicians here know, many of those
> data are simply not accurate the way that they are presented in the
> newspaper and the public media.
>
> There is an inherent risk and we must have risk management, but we
> also have to look at the risk of the alternatives to using opioids if
> we don\'t have opioids available.
>
> \[Slide.\]
>
> Now, the major other systemic class of medications that we are going
> to be using for moderate pain are the nonsteroidal anti-inflammatory
> drugs. We have those, we have the opioids, and beyond that we have a
> whole bunch of adjuncts that are very important, but we have invasive
> procedures, and what is being used as an alternative to opioids,
> invasive central nervous stimulation, invasive implantation of
> catheters into the central nervous system, areas where we largely have
> no evidence to support efficacy, where we have solid evidence for the
> opioids.
>
> \[Slide.\]
>
> Indeed, in 1998, the last year, before we had COX-2 selective NSAIDs,
> looking at the reported number of adverse drug events reported to the
> Food and Drug Administration, we know that NSAIDs are the number 1
> category, we had over 125 million prescribed opioids, and we had major
> gastroduodenal and platelet toxicities resulting from these, which
> mandates this warning from the Agency.
>
> \[Slide.\]
>
> We are all familiar with this. It is an important warning. These drugs
> have real risk. They are wonderful medications, I have never said take
> them off the market or restrict their use. We have to use them within
> a risk:benefit consideration.
>
> \[Slide.\]
>
> In 1998, we had 107,000 documented hospitalizations and 16,500 deaths
> due to NSAID-induced gut bleeds in this country with endoscopically
> documented lesions.
>
> So, the issue here comes down to risk:benefit ratio, and I believe
> that is the way that the committee might best look at how these
> opioids are going to be used.
>
> \[Slide.\]
>
> If we don\'t have opioids available, this is what is going to be used,
> invasive procedures that are not supported by evidence, and as every
> pain clinician knows, there are aggressive lobby groups trying to get
> massive reimbursement from this from CMS.
>
> \[Slide.\]
>
> Now, the opioid concerns are multiple, and my time precludes my
> getting into these at depth, but you have members of your committee,
> like Dr. Portenoy, who studied these extensively and are well aware of
> the fact that these are the perceived problems, but that, to a great
> extent, they are exaggerated concerns.
>
> \[Slide.\]
>
> Addiction in the context of pain treatment with opioids was defined in
> the public statement of the American Society of Addiction Medicine in
> its Public Policy Statement\--this is on the web at asam.org\--in this
> manner, a definition with which I think all of us can live.
>
> \[Slide.\]
>
> But what is critically important is to recognize that ASAM went on to
> say that patients may appear to observers to be preoccupied with
> obtaining opioids, but the preoccupation is with finding relief of
> pain, not with opioids per se.
>
> In 1997, ASAM endorsed the Weisman and Haddox iatrogenic syndrome that
> they defined in their classic paper in the journal Pain in 1989 as
> pseudoaddiction.
>
> I very much appreciate the introductory presentation from CDER in
> which the problem was defined as complex with a very important caveat.
> There is no simple solution. I get very concerned when I hear
> individuals come up and try to propose a simple solution, a single
> solution, such as restriction to severe pain. Science absolutely does
> not support that, absolutely does not support that, or other types of
> restrictions that clearly would minimize availability for patients who
> need these.
>
> \[Slide.\]
>
> Tolerance is held up as a huge issue. In the new edition of Carol
> Warfield\'s Textbook on Principles and Practices of Pain Management
> just coming out this summer or actually this fall, we recognize that
> tolerance to analgesia is very different to the other tolerance
> issues. The mythology that has already been referred to by earlier
> speakers is what drives so many decisions.
>
> \[Slide.\]
>
> In fact, if we look at opioids dose requirements, work that we did in
> England in the mid-1970s, that Robert Twycross published in the
> International Journal of Clinical Pharmacology, this was an individual
> we were treating with diamorphine, a legitimate drug in the United
> Kingdom, that is heroin, of course, and the dose went way up and then
> came down, and went up and came down before this patient with advanced
> irreversible cancer died.
>
> Starting patients on opioids at whatever dose is necessary does not
> condemn patients to ever-increasing doses, nor does it carry the risks
> that we all know so well in the acute setting. In fact, again, I defer
> here to people like Russ Portenoy who know this field better than I
> do, how well patients become tolerant to some degree to respiratory
> effects after just five to seven days of regularly scheduled opioids.
>
> Are people dying from misuse of substances? Absolutely. Are people
> dying from misuse of many noncontrolled substances? Absolutely. That
> doesn\'t mean we take the substance away.
>
> \[Slide.\]
>
> Acutely, opioids are profound respiratory depressants. Within a week
> of initiating therapy, opioid tolerance is so great that in a 1996
> book that Professor Margaret Batten \[ph\] and I published on Drug Use
> and Assisted Suicide and Euthanasia, we had a chapter from Dr. Steven
> Jamison, who studied a cohort of patients who went on to die due to
> AIDS, who tried to kill themselves or their partners tried to kill
> them, assisted suicide, using opioids, and they couldn\'t do it
> because these patients were tolerant to the opioid respiratory effect.
> These people were suffocated with a drycleaning bag or a pillow in
> some cases.
>
> This is the type of tragedy that comes from the type of emotional
> mythology that unfortunately drives political decisions, but
> hopefully, does not drive scientific decisions.
>
> \[Slide.\]
>
> Patients skip analgesic doses. The literature on this is very clear.
> None of us, thank heaven, can recall the experience of severe pain. We
> can recall having been in pain, but we don\'t recall severe pain, and
> we have good studies that show that patients start skipping doses.
>
> Well, what happens? In this classic cartoon that Twycross published
> three decades ago, the idea was to keep the patient within the
> therapeutic window, shown here, but what in reality happens with
> short-acting medications is people having to take two, three, four
> doses a day, are more apt to skip doses as the number of doses per day
> goes up.
>
> \[Slide.\]
>
> Of course, the new science that has come out, and I have given you a
> couple of references here, and I have intentionally given you good
> reviews of the primary literature, both physiological windup, the
> augmented response to repetitive firing of the nociceptive neuron, and
> even more importantly, neuronal plasticity, the changes with the
> central nervous system and peripheral nervous system, but primarily
> the CNS, that occur in humans as a result of undertreated pain are
> such huge issues that we need to be more aggressive, not less
> aggressive in treating pain.
>
> Has opioid use gone up? Absolutely. Is much of that opioid increased
> use appropriate? Absolutely. Are we using enough opioids to treat
> severe and moderate pain today? Probably not.
>
> Is there abuse? Of course, there is, but let\'s not look at numerator
> data without looking at appropriate denominators, as well.
>
> \[Slide.\]
>
> Do we need alternatives? Absolutely. Methadone clearly is the drug.
> When I was an investigator on the National Cancer Institute
> demonstration project of hospice care that we did in the 1970s, when I
> was at Yale, that was the one opioid that we used - wonderful
> medication, profoundly effective analgesic, but we had nurse
> investigators who visited with the patients twice a day.
>
> \[Slide.\]
>
> Methadone, as many of you know, has a biphasic elimination with very
> unpredictable pharmacokinetics and a serious risk of accumulation
> toxicity.
>
> \[Slide.\]
>
> Indeed, this is a computer-generated plot that we did in our computer
> modeling, in which we show the very, very long beta elimination
> half-life. Now, why is that important clinically? Because it will take
> perhaps 10 days to get to steady-state serum levels, and the risk of
> accumulation toxicity is huge.
>
> In the State of Oregon where, under CMS regulations, physicians are
> required for Medicaid patients to use methadone in lieu of
> pharmaceutically long-acting opioids, which have very different
> dose-response curves, there have been, I am told, and I have not seen
> the original data, but I have been told by physicians who I believe
> that there have been increased numbers of deaths due to methadone
> toxicity, accumulation toxicity, a far more difficult drug to use
> pharmacokinetically than the pharmaceutically made long-acting dosage
> forms.
>
> \[Slide.\]
>
> Here is a huge myth. Can patients drive safely? Dr. David Fishbain,
> Professor of Psychiatry and Adjunct Professor of Anesthesiology and
> Neurosurgery at the University of Miami, published a systematic
> review, and extensive valid systematic review in the journal that I
> edit a year ago, looking at the entire world literature, and most
> people taking opioids can, in fact, drive safely after they have been
> on consistent doses.
>
> Of course, Professor Vainio of Helsinki demonstrated this first in her
> classic paper in the Lancet in 1995. There are a dozen other papers
> out that I could cite, actually 27 in total. The key here is I believe
> that we have to put opioids in perspective.
>
> If we start restricting opioids to a given class of prescribers, I
> think we will have a public health disaster on our hands. I have just
> finished a textbook entitled, \"Pain Management for Primary Care
> Clinicians.\" A good friend of mine and of several of you on this
> panel, Dr. Bill McCarberg \[ph\], who is a family practitioner and a
> diplomate of the American Board of Pain Medicine, who runs the pain
> service and does primary care at Kaiser Permanente in San Diego, wrote
> the preface.
>
> Bill emphasized in this book, the absolute importance of primary care
> clinicians, family practitioners, internists, physician assistants,
> advance practice nurses who are so licensed, having access to the
> right modalities to treating pain.
>
> I appreciate what the DEA said, education is critical and many of the
> other things that the DEA representative said are critical, but the
> science and the epidemiology and the clinical need do not support
> restricting to any one group of prescribers, nor to any one category
> of pain.
>
> Opioids are actually safer vis-a-vis end organs than either NSAIDs or
> acetaminophen. Acetaminophen, as every clinician knows, has the
> potential of hepatotoxicity, and whether it is a COX-2 selective NSAID
> or a non-selective NSAID, there still are inherent risks, but there
> are risks with every drug.
>
> Acutely, opioids are very toxic chronically, when they are taken
> within the label, are actually relatively safe. I don\'t believe that
> anyone in this room individually can prevent people from taking drugs
> inappropriately. We do need good risk management programs, I strongly
> applaud that, but I don\'t believe that it would be conscionable to
> take away access to opioids.
>
> \[Slide.\]
>
> The AHCPR, now renamed the Agency for Healthcare Research and Quality,
> the American Society of Anesthesiologists, the American Academy of
> Pain Medicine, the American Pain Society, American Society of
> Addiction Medicine, American Geriatric Society have all come out with
> documents strongly advocating the use of opioids in appropriate
> clinical settings, and not, implicitly not restricting these because
> most of the patients who are going to be seen with osteoarthritis, a
> small percentage of whom will be require opioids, not a large
> percentage, but a small percentage, they are going to be seen by
> primary care clinicians, they are not going to be seen by
> rheumatologists.
>
> \[Slide.\]
>
> I want to save time for questions because I think this is a very
> important issue. I feel strongly about it, but my passion is not based
> upon clinical emotion, it is based upon what the evidence says.
>
> Liebeskind and Melzack went on to say that this pain that people are
> suffering is needless, it impoverishes the quality of life of patients
> and families. It shortens life because it impairs recovery, that is
> the catabolism and the emotional issues.
>
> People become depressed, they lose their will to live, they fail to
> take normal health-preserving measures. Before he went to prison in
> Michigan several years ago, Jack Kevorkian\--I think everyone
> remembers Dr. Jack Kevorkian, the pathologist who was affectionately
> known in Michigan as Dr. Death\--I am told by a physician colleague, a
> pain specialist in the Midwest, that Dr. Kevorkian\'s\--and this is
> one who has access to the information-that Dr. Kevorkian\'s answering
> service was receiving over 1,000 telephone inquiries a week before he
> went to prison.
>
> Now, there were not 1,000 people looking to end their lives. These
> were 1,000 people who wanted to explore whether active end of life was
> an alternative that they should have available. What is fascinating is
> that the vast majority of these patients did not have advanced
> irreversible disease, they didn\'t have cancer, they didn\'t have
> AIDS, they had low back pain, they had arthritic pain, and they had
> headache pain.
>
> We are talking about approximately 50 million people in the United
> States per year experiencing either intermittent or fairly continuous
> chronic pain. Opioids are not first-line therapy, we all know that,
> and responsible clinicians do not advocate them as first-line therapy
> in most chronic, nonmalignant pain.
>
> But just as recently as a decade and a half ago, there was general
> belief among many clinicians that opioids had no place in chronic,
> nonmalignant pain. Now, we have grudgingly seen the medical community
> accept, based on evidence, the appropriateness of opioids in cancer
> pain and in acute pain, and those are clearly documented in a
> searchable format in those two Department of Health and Human
> Services\' Public Health Service Clinical Practice Guidelines.
>
> The Cancer Pain Guideline, by the way, is under revision right now
> through the American Pain Society, and actually, there is more
> evidence to support opioids there, there is no question.
>
> Again, I tip my hat to Dr. Portenoy for the seminal work that he did
> during the 1990s, getting the world pain community to look at the
> serious question of risk:benefit ratio of opioids in chronic,
> nonmalignant pain, and a large body of research that has taken place
> in the past decade has clearly shown that there definitely is a place
> for opioids in chronic, nonmalignant pain, not just severe pain.
>
> We do not have the resources, and should not have the resources in
> this country, for all people who have moderate to severe pain to be
> seen by pain specialists. It would be very good for my clinic and it
> would be very good for some of the other people here\'s clinics, but
> that is not reality.
>
> We do need education, we do need risk:benefit decisions, and we do
> need risk management programs, but I am here to speak on behalf of
> Joshua, both the Joshua to whom the congressman referred, and to my
> son Joshua, who is 8 years old, and all the other Joshuas and other
> people in this country who at some time in their lives may require
> opioids to assure that we have the most reasonable dosage forms.
>
> The pharmaceutics has improved dramatically. The entire science of
> pharmaceutics, of dosage form development, of making medications that
> will release on a consistent basis, that will give us both an
> immediate release and an controlled release phase, has advanced by
> orders of magnitude in the past 15 years, and, indeed, some of the
> newer dosage forms that we have are far better than some of the older
> ones.
>
> The only other thing I would like to leave with the Committee from
> conversations that I have had with health authorities in the states
> that have been impacted by some of these disastrous multi-drug, not
> single-drug abuse situations often leading to death, is the fact that
> in the majority of those cases, as I understand it, number one, there
> was no autopsy toxicology data, so we don\'t even know what the
> substance was, there is clear evidence of polysubstance abuse, and
> even when a particular opioid, be it hydrocodone or oxycodone or
> morphine or fentanyl, whichever one was found, as you all know, from
> autopsy data, there is no way to ascertain the dosage form that caused
> that unless we actually we find ghosts of that dosage form within the
> gastrointestinal system of the decedent or actually find tablets or
> capsules on the body, and that has rarely been the case.
>
> So, these huge emotional extrapolations that we have seen, I think
> have to a great extent clouded the science, and I hope that the
> decisions that are made here within the tradition of the FDA and
> within the traditions of the Public Health Service will be based on
> the best issues of public health for the American citizens.
>
> With that, I would be happy to take any questions or comments from the
> committee members.
>
> DR. KATZ: Thanks, Art. We do have time for a couple of questions. What
> I would like to be clear on, though, is that I think the most
> appropriate scope for any questions now would be on the evidence base
> for the use of opioids for chronic pain, and I would prefer to defer
> any discussion of the specifics of risk management plans, pros and
> cons, restricted labeling, all that thing, there will be ample time
> for discussion of that in the afternoon and tomorrow.
>
> So, any questions about the evidence base for the use of opioids or
> alternatives in chronic pain? Dr. Shafer.
>
> DR. SHAFER: First, thanks, I enjoyed that presentation immensely.
>
> We have earlier today identification of specific molecule oxycodone
> and concerns about the risk of oxycodone. Are you aware of any data to
> suggest that any molecule in the Class II category has more abuse
> liability than any other molecule just related to the intrinsic
> pharmacology, not in terms of availability and distribution?
>
> DR. LIPMAN: Yes. That\'s an excellent question and I am aware of the
> data, and the data say that that is absolutely not the case. Oxycodone
> is no more dangerous than morphine, is no more dangerous than
> fentanyl, is no more dangerous than hydromorphone.
>
> A very important point, however, is that Dr. Gabriel Pasternak has
> done some extremely important genetic research with a mouse knockout
> model, the Kopeki model, in which he has now demonstrated\--and, Russ,
> you can tell me the latest number\--the last time I talked to Gab, I
> think it was about 14 different subsets. It is higher than that, he
> tells me now. Well over a dozen subsets of the mu-1 receptor.
>
> Now, what does this mean and how does it relate to your question? All
> of us in this room have receptors within our central nervous system at
> which opioids work, and the specific receptor at which a mu agonist
> opioid, which, of course, includes morphine, oxycodone, and most of
> the other Schedule II controlled substances we have discussed here
> today, at which they bind to give us the analgesic and other activity
> are mu receptors and specifically mu-1 receptors.
>
> Now, what Dr. Pasternak\'s work, both as a neuropharmacologist and a
> neurologist, he has done elegant research, and he has shown that there
> are differences in the density of the subsets of the various receptors
> in different patients.
>
> Now, what this means is that I may respond more to morphine, both
> clinically and toxicologically, Nat may respond more to oxycodone, and
> someone else may respond more to hydromorphone, but it also means
> clinically that we need, and I emphasize the word \"need,\"
> alternative opioids.
>
> There is now a genetic polymorphism, scientific basis for serial
> trials of multiple opioids and not to conclude that a patient who
> fails one opioid will necessarily fail another even though they are
> both mu agonists.
>
> As far as the toxicology on your specific question, no, absolutely
> not. There is no greater risk, in fact, there is less risk chronically
> with oxycodone than with morphine because we don\'t have a potentially
> neuro-irritant metabolite, in the case of morphine,
> morphine-3-glucuronide, and we only have one small percentage
> clinically effective metabolite with oxycodone, that is oxymorphone,
> and it has the same elimination pattern as the parent compound, so
> there is no accumulation risk. So, it is actually a safer drug from a
> molecular perspective.
>
> DR. KATZ: Dr. Skipper, you are next.
>
> DR. SKIPPER: Let\'s see, we were given a report from the Research
> America this morning, which says that a poll shows that 57 percent of
> Americans suffered from chronic or recurrent pain in the past year.
>
> You showed a slide that said freedom from pain should be a basic human
> right. So, would we extrapolate then to suggest that we should be
> treating 57 percent of Americans?
>
> DR. LIPMAN: Not with opioids.
>
> DR. SKIPPER: So, how do we determine where the cutoff is in the
> interaction of other problems like depression, and so forth, that may
> not be due to the pain?
>
> DR. LIPMAN: I think that is a very important clinical question and I
> am not here to write policy for state medical boards. I have spent a
> lot of time in the UK and a lot of time in Scandinavia where there are
> national health systems, and the Federal Government tells clinicians
> how to practice.
>
> Our system works better in many ways, it also has deficiencies that
> they don\'t have, but the issue here is that\'s an individual
> clinician decision dealing with his or her patient. For most patients
> with low back pain, that\'s myofascial, as we all know, stretching is
> the treatment of choice, not opioids, and I am not here to advocate
> wholesale use of opioids.
>
> I am here to say that we have an epidemic, and it\'s not Lipman
> talking, David Satcher, the former Surgeon General, and Louis
> Sullivan, the former Secretary of Health and Human Services, just a
> week ago had a press conference that led to this huge issue, and you
> can find information on painfoundation.org on the web, the American
> Pain Foundation web site, saying that this is still a huge epidemic
> problem in the United States, chronic pain.
>
> Opioids are one important arrow in the quiver. It is critical that we
> keep that arrow sharp and available. It is also critical that these be
> used rationally, and not in a wholesale or first-case manner, but that
> is an educational issue and a state regulatory issue.
>
> Just one closing comment that I think is critical. I heard some very
> telling points earlier. The representative from the DEA told us that
> the vast majority of problems are on the local level. That has to be
> controlled, under the United States Constitution, on a local level.
>
> If we stop the source of critically needed medications on a federal
> level because of inadequate resources or whatever, and I don\'t know
> the answer, to solve local problems, then, I think we are doing a
> terrible disservice to the American public.
>
> DR. KATZ: Again, I would like to remind the committee that I think the
> best focus of the discussion right now is on the clinical issues and
> on the evidence behind it, and we should defer discussion of the
> policy issues until later.
>
> Dr. Leiderman, you are next.
>
> DR. LEIDERMAN: I just have two questions for Dr. Lipman. One, you
> alluded to the immunological suppressant effects, and you said pain.
> The reference that I thought I saw up there was for an article
> entitled, \"Acute and Cancer Pain.\" So, I had a question about
> whether there were data in chronic pain, as well.
>
> DR. LIPMAN: Yes, there are.
>
> DR. LEIDERMAN: Okay. Then, my second question is you also alluded to
> the high suicide rate in untreated pain, and again I wondered if you
> had any data on that.
>
> DR. LIPMAN: Unfortunately, we don\'t have good data, I am not aware of
> good data in the latter area although my friend and colleague, Dr.
> Passik, will be speaking later, may know something, put you on the
> spot, Steve, because I think he has looked at these areas far more
> than I have.
>
> The question you asked, though, is excellent. There is a good-sized
> literature that is growing rapidly now on suppression particularly of
> natural killer cells, but of host defenses from pain much more so than
> with opioids. Opioids, as you know, have a mild effect on NK cell
> counts, pain has a much more serious effect NK cell counts. In fact,
> we have a manuscript in preparation right now that will be coming out
> within the next six months, a systematic review of the entire world
> literature on that issue.
>
> We have six different immunological indicators showing that with a
> whole range of human clinical chronic pain models, there are cell
> count shifts and other issues that do need to be looked at. If you
> would like details on that, just drop me an e-mail, I would be happy
> to share that with you.
>
> DR. KATZ: Dr. Bril.
>
> DR. BRIL: Thank you for an excellent presentation. I think in acute
> and terminal cancer pain, it is kind of easy to consider Class II
> drugs. My question really had to do around chronic pain models and,
> because of my interests, say, chronic diabetic neuropathy pain or
> chronic neuropathy pain, which is as severe a problem to the patients
> as other forms of pain.
>
> But I wonder how good the evidence is or what the relative efficacy is
> of, say, a Class II agent compared to an adjuvant analgesic and how
> necessary this class of compound is in this indication.
>
> I mean are there good comparative studies, what is the science that
> would say you would want someone chronically to take, say, oxycodone
> or MS Contin, or whatever?
>
> DR. LIPMAN: No, there are not good comparative studies looking at
> tricyclic antidepressants versus antiepileptic drugs versus opioids.
> There are, however, good serial trials, and the best data set that I
> am aware of here is that that belongs to Mitchell Max, whose clinic is
> right up the street here at the NIH.
>
> Mitchell, as you know, is a neurologist who runs the analgesic trials
> clinic at the clinical center, and he has looked at a whole range of
> painful diabetic neuropathy and other neuropathy models.
>
> In answer to your question, yes, there is an absolute need for
> opioids. Now, if you look at the paper that came out in Pain in 1988,
> out of Stockholm, in which Arner \[ph\] and colleagues said that there
> is no efficacy for opioids in neuropathic pain, you would recognize
> that that work has subsequently been refuted. It was actually a Type 1
> or Type 2 error in the statistical analysis in that study, that
> seemingly well done study, which is why, of course, we require
> repeated studies of pivotal trials for any drug to be approved.
>
> Again, I would defer to Dr. Portenoy as a neurologist. He has done
> some of this work and has shown that there is a clear place. Sometimes
> we require higher doses of opioids, and we don\'t really understand
> the mechanism. It is probably some central plasticity in these
> neuropathic pain models than we would in seemingly comparable
> nociceptive pain, but opioids are definitely effective.
>
> We have dozens of patients on chronic opioids in our clinic including
> some painful diabetic neuropathy, postherpetic neuralgia, and other
> neuropathic pain models. What is interesting is that most of these
> patients are on chronically far, far lower doses of controlled release
> opioids than they required initially to get the pain under control,
> because the anxiety and all the confounds associated with the initial
> pain presentation often lessen once we obtain some pain control for a
> period of time, and particularly when we get them into multimodal
> therapy where they learn coping techniques and they learn some
> relaxation to cut down the sympathetic autonomic input, that the vast
> majority of patients who are on chronic opioids are on relatively low
> doses of long-acting opioids.
>
> DR. KATZ: Maybe to expand on that for a second, there are actually
> several randomized placebo-controlled clinical trials of opioids for
> neuropathic pain that show efficacy, and there is now just recently
> published one, a study from Raja and his colleagues at Hopkins
> comparing, in the same head-to-head placebo-controlled trial,
> tricyclic antidepressant versus opioids and showing that, if anything,
> the opioid group seemed to have better pain control than the tricyclic
> group, and both groups did better than placebo.
>
> Now, these are short-term studies, but that is the database available
> to answer your question.
>
> DR. LIPMAN: I concur with that, but I believe that some of these
> patients, indeed, there is clearly some patients who will respond
> better to opioids and others who will respond better to monoamine
> reuptake inhibitors.
>
> The key is that if we are going to minimize risk, we need to be able
> to combine these therapies, and that is where we need a range of
> dosage forms, and because of the genetic diversity and genetic
> polymorphism, we need a range of different opioids in controlled
> release dosage forms.
>
> DR. KATZ: Thank you very much for your comments. In the interest of
> time, I am going to have to apologize to Dr. Baxter, the second time I
> have cut him off, and Dr. Portenoy. We need to move along with the
> schedule.
>
> I would like to introduce Dr. Gianna Rigoni from Office of
> Pharmacoepidemiology and Statistical Science at FDA, who will be
> speaking with us about opiate use data.
>
> **Opiate Use Data**
>
> DR. RIGONI: Thank you, Dr. Katz.
>
> Today, I would like to describe the patterns of use of immediate and
> modified release opioids in both inpatient and outpatient settings, to
> provide a context for discussions of risk management plans over the
> next two days.
>
> \[Slide.\]
>
> Data on drug utilization will be presented from sources FDA has
> available under various contracts. Outpatient data was obtained from
> two IMS health audits. IMS is a source of marketing data most commonly
> used by the pharmaceutical industry and government agencies to obtain
> the number of dispensed prescriptions in the United States.
>
> Inpatient data was obtained from Premier, a group purchasing
> organization, for approximately 400 hospitals in the United States,
> and will be explained in more detail in a few minutes.
>
> \[Slide.\]
>
> First, I will present data on outpatient drug utilization. We will
> first examine the trends of immediate release opioids when combination
> products like Vicodin, Lortab, Percocet, et cetera, are included.
>
> Then, we will remove these products and examine single-agent,
> immediate release opioids. Lastly, we will examine modified released
> opioids and methadone.
>
> \[Slide.\]
>
> The National Prescription Audit from IMS Health measures dispensed
> prescriptions from retail pharmacy settings seen here in the second
> bullet, and only oral dosage forms were included in this analysis.
>
> The number of dispensed prescriptions is obtained from a sample of
> approximately 22,000 pharmacies in the United States and is projected
> nationally. Mail-order and long-term care pharmacy settings were not
> included in this analysis since they do not capture the physician\'s
> specialty writing the prescription.
>
> \[Slide.\]
>
> Total prescriptions dispensed were selected for opioids relevant to
> the discussions we will be having today and tomorrow, and are
> presented here in millions of prescriptions dispensed. The graph
> categorizes the opioids into immediate release dosage forms,
> represented by the blue line, modified release opioids, by the red
> line, and methadone, by the green line on the bottom.
>
> Methadone was looked at on its own since technically, it is not a
> modified release dosage form, but i is long acting.
>
> This graphs shows a trend of an increasing number of prescriptions
> dispensed in retail pharmacy settings over the past five years for
> Schedule II immediate release and modified release opioids, as well as
> Schedule III immediate release hydrocodone products. Methadone also
> appears to be increasing, but at a slower rate.
>
> I will now zoom on this top line to give you a better picture of what
> is happening with immediate release opioids.
>
> \[Slide.\]
>
> Immediate release opioids, when including combination products, which
> I have mentioned before, are widely used, with hydrocodone having the
> most prescriptions dispensed at approximately 90 million in 2002.
>
> I am now going to remove these combination products and zoom in even
> further on the immediate release single-agent opioids to make a more
> clear distinction between the products dispensed in small volumes here
> on the bottom of the screen.
>
> \[Slide.\]
>
> When we remove the combination products, we see more clearly the total
> prescriptions dispensed have increased over the last five years, but
> at a much lower volume, about less than 2 million prescriptions per
> year.
>
> \[Slide.\]
>
> This graph represents the modified release opioids and methadone. It
> appears here also that total prescriptions dispensed have been
> increasing over the last five years, but again in lower volumes, less
> than about 7 million per year we see here, and modified release
> oxycodone growth appears to be leveling off as of year-end 2002.
>
> Now that we better understand the trends in dispensed prescriptions
> for immediate release and modified release opioids, we need to better
> understand which physician specialties most often prescribe these
> products.
>
> \[Slide.\]
>
> The top prescribing specialties in 1998 were compared to the top
> prescribing specialties in 2002, and each specialty is represented by
> a different color bar.
>
> Here, it makes sense to see dentistry among the top two prescribers
> over time since combination products are included in this table. There
> appears to be no significant change in prescribers over time since the
> same specialties remain in the top two-thirds of prescribers from 1998
> to 2002.
>
> \[Slide.\]
>
> Looking at the same data, but again removing the combination products,
> we see that in 1998, the hematology-oncology specialty made up about
> 25 percent of immediate release opioids prescribers, but dropped to
> about 11 percent in 2002. This does not mean there have been less
> prescriptions dispensed by the hematology-oncology specialty, just
> that more physicians are treating pain in outpatient settings.
>
> Also, keep in mind here that mail-order and long-term care data do not
> include physician specialty, and were not included in this analysis.
> Therefore, we may be underestimating prescribing by specialty, such as
> helonc and physical medicine in rehab.
>
> \[Slide.\]
>
> We see similar trends from 1998 to 2002 for modified-release opioids
> and methadone where primary care physicians constitute a majority of
> the top two-thirds of prescribers.
>
> \[Slide.\]
>
> Next, we examined data from the National Disease and Therapeutic
> Index, or NDTI. NDTI collects data on drug products and indications
> mentioned during office-based physician visits, in other words, a
> physician\'s treatment intention where they believe an opioid is
> appropriate.
>
> NDTI provides information on trends of diagnoses, patients, and
> treatment patterns occurring in office-based practice, and indications
> as reported by the physician are linked to each drug.
>
> Data on office-based physician visits are obtained from a sample of
> approximately 2- to 3,000 physicians in the U.S. and projected
> nationally to reflect national prescribing patterns.
>
> \[Slide.\]
>
> The following graphs display the number of visits to a physician\'s
> office where an opioid was prescribed. All diagnoses naturally fell
> into these four categories - Other Pain, which includes migraine
> headache, fracture, dental pain, complications of pregnancy, any other
> pain.
>
> The second category is postoperative surgical procedures. Third, is
> musculoskeletal pains, such as myalgias, lots of lower back pain, and
> various arthritis, and cancer-related pain down here on the bottom.
>
> The blue bar presents the number of physician office visits in 1998
> compared to the red bar, which is 2002. Since combination products
> make up a majority of this category, we see physician visits in the
> tens of millions across the five years we looked at.
>
> Top indications for 1998 continue to be the top indications for 2002,
> and appear to be increasing over time with the exception of
> cancer-related pain, which is your last bars over there.
>
> I am now going to take out the combination products like I have done
> previously in order to see the immediate-release single agent opioids
> more clearly.
>
> \[Slide.\]
>
> When the combination products are removed, we see the number of
> physician office visits decreases into the hundreds of thousands and
> can see a shift in prescribing over time from Other Pain in 1998 to
> more cancer-related pains in 2002.
>
> \[Slide.\]
>
> Finally, we examine the most frequently occurring indications
> associated with modified-release opioids and methadone, and we once
> again see a shift in prescribing from cancer-related pains in 1998, to
> musculoskeletal pains in 2002.
>
> \[Slide.\]
>
> We have now seen the trends in outpatient use in opioids, we have seen
> an increase in the volume of dispensed prescriptions prescribing
> primarily from primary care providers, and immediate-release opioids
> use more in treating cancer-related pain, while modified-release
> opioids are being used more to treat musculoskeletal pain.
>
> Lastly, we will take a quick look at the use of modified-release
> opioids in inpatient settings to better understand the use of these
> products in conjunction with inpatient surgical procedures.
>
> \[Slide.\]
>
> Premier provides information on inpatient use of drugs from
> approximately 400 acute, short-stay, non-federal hospitals belonging
> to their group purchasing organization or GPO. A GPO is an
> organizational unit which procures and negotiates purchase price
> conditions for this particular group of hospitals.
>
> Premier data includes billing information on patients, drugs, and
> procedures done for every hospital discharge from 2000 to 2002.
> Because this is billing data, there are no direct linkages between
> procedures and drugs, and we can only identify if billing for a drug
> and a procedure occurred on the same day or the day after.
>
> Since it was the intention of this analysis to examine the use of
> modified-release opioids in conjunction with surgical procedures,
> these data are appropriate.
>
> Patients with a discharge diagnosis associated with any type of cancer
> were excluded because we cannot distinguish if they were admitted to
> the hospital already on opioids to treat their cancer-related pain.
>
> \[Slide.\]
>
> This graph shows the percent of all surgical procedures associated
> with a modified-release opioid being billed on the day of or the day
> after surgery. Each bar represents the total number of surgeries
> performed in Premier hospitals in the following years, and the blue
> portion of the bar represents the percent of surgeries where
> modified-release morphine was used in conjunction with a surgical
> procedure.
>
> The red part of the bar is where modified-release fentanyl was used.
> The green part is where modified-release oxycodone was used. The gray
> part of the bar represents the percent of surgeries where none of
> these three products were billed within the same time frame that I
> mentioned before.
>
> We see there is a substantial use of modified-release opioids
> associated with inpatient surgeries over the last three years.
> Modified-release opioids have consistently been billed on the day of
> or day after surgery 50 percent of the time in Premier hospitals with
> modified-release oxycodone being ordered most frequently.
>
> Next, we looked at the most frequently performed surgical procedures
> in these hospitals to see how modified-release opioids were used in
> conjunction.
>
> \[Slide.\]
>
> These are the top three surgical procedures done in Premier hospitals
> from 2000 to 2002, and the percent of time a modified-release opioid
> was billed on the same day or day after.
>
> The green bar represents the most frequently occurring operations in
> Premier hospitals, and that being musculoskeletal operations, the most
> common being total lower extremity replacements.
>
> The red bar signifies second most common surgical procedures -
> genitourinary operations, the most common being hysterectomy, and the
> blue bar represents digestive system operations, the most common being
> cholecystectomy.
>
> As we can see, the percent of surgery is where modified-release opioid
> occurred has remained constant over time, but 35 to 65 percent of the
> top three most common surgical procedures are associated with
> modified-release opioid use.
>
> \[Slide.\]
>
> Some limitations of our analysis for the outpatient drug use data are,
> first, data on dispensed prescriptions include prescriptions filled in
> retail pharmacies only. We excluded mail-order and long-term care
> pharmacies in this analysis, and data from methadone maintenance
> clinics are not included in these data.
>
> Second, data on indications for opioid use reflect office-based
> physicians\' prescribing based on a small sample size of physicians,
> which does not mean a patient actually filled the opioid prescription,
> and the small sample size makes these numbers unstable.
>
> With inpatient drug use data, because using billing of medications and
> procedures as proxy for actual clinical care may be imprecise, we
> could be over- or underestimating modified-release opioid use with
> surgical procedures.
>
> Since Premier data represents only patients admitted into the hospital
> that have a surgical procedure, same-day surgeries are not included,
> which may represent a substantial number of surgical procedures.
>
> \[Slide.\]
>
> In conclusion, use of opioids appears to be increasing in outpatient
> settings and is widespread in inpatient settings. Primary care
> providers continue to be the leading prescribers of opioids in the
> outpatient setting.
>
> Indications for the outpatient use of opioids has shifted for
> immediate-release opioids from treating Other Pains to treating more
> cancer-related pain, and from modified-release opioids has shifted
> from treating cancer-related pains to treating more musculoskeletal
> pain.
>
> Therefore, when considering risk management strategies over the next
> two days, we need to keep in mind that immediate- and modified-release
> opioids are not prescribed by any single prescriber in any single
> setting or for any single indication in the United States.
>
> Thank you.
>
> DR. KATZ: Any questions?
>
> I have a question. Do any of the databases that were analyses that you
> have looked at give us any insight or give us any national projections
> on the number of individuals in the United States that appear to have
> been on long-term opioid therapy?
>
> DR. RIGONI: That, we would require probably more of a longitudinal
> database. We just kind of have snapshot looks at data available to us
> right now. We would have to do further analysis for that.
>
> DR. KATZ: Any other questions? Yes, Dr. Jenkins.
>
> DR. JENKINS: For the data on the inpatient use postsurgical, were you
> able to determine whether those patients were receiving the
> modified-release opioid before they had the surgical procedure?
>
> DR. RIGONI: No, that unfortunately was one of the limitations of using
> this data. We were not able to see the drugs they came into the
> hospital on, which is why we excluded cancer patients because we
> thought that would muddy up the analysis.
>
> DR. KAHANA: Were there any regional differences, were you able to
> stratify what part of the country the modified-release products were
> being used, are they in one part of the country, is there a specific
> area that they are more prevalently prescribed?
>
> DR. RIGONI: Actually, we didn\'t look at that either. That is
> something not available in our contract with our data vendor, so we
> weren\'t able to examine that.
>
> DR. KAHANA: So, you don\'t know where these patients were?
>
> DR. RIGONI: Right, we don\'t. These are just national estimates.
>
> DR. KATZ: Dr. Shafer.
>
> DR. SHAFER: Just a follow-up to Dr. Jenkins\' question. I hate to
> extrapolate from an N of 1 situation, but I was very surprised to see,
> for example, 10 percent of post-op patients getting Duragesic, because
> I know that in our practice at Stanford, which is the N of 1, you just
> don\'t see it because of the Black Box warning.
>
> So, I do wonder about those post-op surgical data and I don\'t know if
> other people would have similar experiences.
>
> DR. RIGONI: I agree with you. We really didn\'t have that much extra
> data on these patients to be able to kind of figure out if it was used
> for that or that they came in on a Duragesic patch for some chronic
> pain that they had before, so it is yet another limitation of using
> that data in this analysis.
>
> DR. KATZ: Dr. Portenoy.
>
> DR. PORTENOY: I was surprised also at the prevalence of use of the
> modified-release for postoperative pain. You might not have the
> answers to this, but are there any other databases that might evaluate
> risk in that subset and help us understand what is happening with that
> subset of patients?
>
> DR. RIGONI: In the hospital setting?
>
> DR. PORTENOY: I gathered that many of those patients might have gone
> home with those drugs. The data only assessed whether or not a drug
> was prescribed the day after an operation. I would guess that many of
> those patients were prescribed those drugs on discharge. That seems to
> be a common pattern in my hospital. I would guess that is probably
> what happened.
>
> But most of those patients most likely were not using opioid therapy
> before, so they were at a relatively higher risk of adverse events,
> and I just wondered whether there is any database that looks at that
> population specifically in terms of risk after discharge.
>
> DR. RIGONI: Not that I am aware of. We are still exploring the Premier
> database in the Office of Drug Safety at FDA to see if we might be
> able to tease that out of that data, but we have been working with
> them quite closely to try to figure out if we can determine that from
> their data.
>
> DR. KATZ: Dr. Strom.
>
> DR. STROM: Just in answer to that, longitudinal databases, like
> managed care or Medicaid databases, could answer that question. They
> wouldn\'t have the information on the inpatient drug use, but you
> would be able to look, of all those people who were discharged after a
> surgical procedure on long-term opiates, what proportion of them had
> come in on it to begin with.
>
> DR. RIGONI: We, unfortunately, don\'t have some of those data
> available to us.
>
> DR. KATZ: Thank you very much for sharing that data with us, we all
> appreciate that.
>
> Next, it is my pleasure to introduce Steven Passik, who is the
> Director of Palliative Care Research\--Steve, is that right\--at the
> Markey Cancer Center?
>
> DR. PASSIK: Yes.
>
> DR. KATZ: Dr. Passik has been a long-standing contributor in the area
> of pain management and particularly in patients with substance abuse,
> and will be speaking with us about Misuse and Abuse of Opiate
> Analgesics in the Medical Setting.
>
> **Misuse and Abuse of Opiate Analgesics**
>
> **in the Medical Setting**
>
> DR. PASSIK: Thanks, Nat, it is a pleasure and really an honor to be
> here to put my two cents in, in this dialogue. I had a little trouble
> finding the room. I live in Lexington, Kentucky, and the next town
> over is Versailles, Kentucky, so when I asked where the Versailles
> Room was, I didn\'t get the right directions.
>
> \[Slide.\]
>
> I wanted to just say by introduction, I started out interested in this
> topic, I started out my career, the first 10 years of which was spent
> at Sloan-Kettering, I had the honor of working with Russ Portenoy,
> Kathy Foley, and Bill Breitbart and others, and was interested in the
> management of pain in addicts as the AIDS epidemic hit New York and
> hit Sloan Kettering.
>
> But subsequently, as this revolution has gone on in pain management
> societally and medically, I became interested in issues related to how
> pain patients sometimes misuse their medicines and issues surrounding
> that problem.
>
> I have to say that the revolution that has happened, in my opinion,
> with the broader use of opioids has absolutely changed the lives for
> the better of, no question, millions of people, but unfortunately, I
> think we have too much rhetoric sometimes in the pain community, and
> that rhetoric has sometimes trivialized the issue of negative
> outcomes, and I think we need to study these issues.
>
> I don\'t know personally that monitoring or restricting is the answer,
> I think we need more research, and I am going to walk you through some
> research studies that we have performed looking at this issue of
> noncompliance behavior in pain patients.
>
> \[Slide.\]
>
> But before I do, I wanted to first say that I am going to try to
> address for a moment the issues of who or what should be monitored. As
> we try to get a count of the problems of bad outcomes in pain
> management, there are several different populations that would be
> affected if changes in policy and changes in clinical practice were
> instituted.
>
> I will admit at the outset that long-term studies of outcomes, good or
> bad, in opioid therapy are virtually absent, and this is a terrible
> problem at a time like right now when we don\'t have data on patients
> who have been on these medicines for months or years. Most of the
> trials that we do have are considerably short than that.
>
> Aberrant behaviors, or the so-called \"noncompliant\" behaviors, their
> frequency, their meaning in the clinical setting, and so on, have been
> poorly studied. That has been the focus of my work, and I will show
> you some of the results there.
>
> Then, importantly, I think the relationship between aberrant behavior,
> namely, when you see noncompliant behavior in a pain patient and
> something has gone awry in pain management, the question is how often
> is that associated with addiction, and we really don\'t know the
> answer there either.
>
> So, to the issue of who or what should be monitored, if I was better
> with PowerPoint, this would be a series of complicated ven diagrams
> with some overlap, and I will leave that to your imagination.
>
> But when we start talking about who or what should be managed through
> risk management, monitored through monitoring programs, or to whom
> drugs will be restricted, we are actually talking about several
> different populations.
>
> I am concerned that the top group, the pain patients, would suffer if
> measures to stop abuse or diversion in some of these other groups were
> instituted. One of the problems we have when you set up a pain
> practice or if you are a primary care doctor who treats a lot of pain,
> is that some people, the people on this first line, will see on your
> shingle where it says, \"Pain Expert,\" they will see hope and
> deliverance, and then other people will see large quantities of
> high-quality opioids available.
>
> The problem is that any steps we take will impact all of these groups.
> All of them, in various forms, do present in pain practices from time
> to time, and I think it is essential really to study these bad
> outcomes, and outcomes related to the aberrant drug-taking behavior
> spectrum, that I will describe, and also better understand when those
> outcomes are actually related to these other groups.
>
> \[Slide.\]
>
> What do we mean by a \"good\" outcome? I apologize to everybody who
> has heard me speak about this before, because of the fact that I have
> been talking about this for years now, the so-called \"Four A\'s\" of
> pain treatment outcomes. Some of the people who have heard me before
> want to add a fifth, which would be \"ad nauseam.\"
>
> But basically, what we have tried to teach the pain community and
> others who treat pain is that we are trying to get a good outcome in
> four areas. We are trying to provide analgesia, we are trying to
> improve psychosocial functioning, we are trying to limit adverse
> effects, and monitor and contain any suggestion of aberrant
> drug-related behavior.
>
> I think the studies that I have done have shown basically that
> analgesia is modest, but meaningful on opioids, meaningful insofar as
> the fact that some 80 percent in one of my studies were rated as
> improved in their overall function, side effects seemed to be common
> but tolerable.
>
> Then, with regard to noncompliant behavior, they are not infrequent.
> The problem is we don\'t always know their meaning, nor do we know
> when they are serious, and that is really I think one of the big gaps
> is that clinicians need more education and more data to understand
> these better.
>
> \[Slide.\]
>
> When I refer to \"aberrant drug-taking behavior, I am referring to
> something like this. This is well known in the pain field now, for
> some of you, though, it might be new. This comes from an observation
> from Russ Portenoy from many years ago, actually first, I believe in
> the late \'80s when he was writing for Jerry Jaffe\'s Textbook on
> Substance Abuse, and this I think is really a brilliant observation
> that Russ had, that has led to a model that we have used in our
> research, as well as in our clinical monitoring of people in chronic
> pain who are on opioids.
>
> What I think Russ was onto quite some time ago was that the
> phenomenology of the physician treating pain is not the phenomenology
> of the addiction medicine specialist. For example, there are many ways
> in which the phenomenology of the addiction medicine specialist has
> been highlighted over and over again as misleading in the pain
> treatment setting.
>
> For example, the patient who develops physiological dependence, we
> know that in the pain setting, that is not associated generally with
> aberrant behavior. Tolerance, to the extent that it develops, is more
> often than not, not associated with aberrant behavior.
>
> So, there are some aspects of the phenomenology of addiction that
> don\'t suit the pain management setting, so sometime ago, we started
> writing about and researching from the point of view of articulating
> our own phenomenology.
>
> Our phenomenology is very poorly studied, but basically, Russ\'s
> observation was that essentially, there is a wide range of aberrant
> behavior that could become evident in the clinical practice setting of
> pain management and that some of it is rather innocuous and some of it
> is very serious, and clinicians need to know how to assess and talk to
> patients about this, researchers need to take up the cause and try to
> figure out how common these things are, and so on.
>
> I would venture a guess that there is more of a literature on
> noncompliance with antihypertensives than there is with opioids. There
> is a lot of rhetoric and there is a lot of emotion, but there is not a
> lot of research on what do people actually do with pain medicine when
> the treatment has gone awry in any way, shape, or form.
>
> \[Slide.\]
>
> One of the big complications we have, the clinician has this
> complication every day when he has a patient in front of him who is
> losing prescriptions, raising their dose on their own, doing anything
> of the kind.
>
> The clinician faces this dilemma and then we, as researchers, face a
> dilemma when we try to understand what do we think this behavior
> means, because it appears in the clinical setting as the end result of
> multiple forces, sometimes more than one at the same time.
>
> Sometimes when a pain patient is misusing their medicines or having a
> bad outcome in this spectrum, it represents addiction or abuse that is
> unfolding in front of the clinician\'s eyes. Sometimes, as Dr. Lipman
> said, it is pseudo-addiction and the patient is acting in an
> uncharacteristic fashion because they have inadequate pain relief.
>
> Sometimes there is a form of self-medication going on or what Eduardo
> Bruere \[ph\] has termed \"chemical coping\" of other life
> circumstance and psychiatric problems, and I would venture a guess,
> although this has also been poorly studied, that there are a lot more
> bad outcomes in this category than there are in the addiction or abuse
> category if you to pain specialists who treat really complicated pain
> patients, because of the psychiatric comorbidities and other problems
> that pain patients sometimes bring with them.
>
> These kinds of problems are more frequently encountered in my practice
> and probably others than are out and out addiction or abuse. Then, of
> course, there is criminal intent. There are people who are presenting
> in a pain clinic with intent to divert.
>
> When these patients are in front of us, this is our dilemma. We try to
> figure out what this behavior means. It is my observation clinically
> and through the research that there aren\'t really any behaviors, even
> the ones that are illegal on their face value, that point you in a
> particular direction.
>
> For example, even the really serious ones where we wouldn\'t very
> often cut a lot of slack, I mean there are certain behaviors that
> really do merit a one-strike-and-you-are-out of the clinic kind of
> policy, like forging a prescription or where there is evidence of
> selling your medication, and so on, versus simply running out a day or
> two early, so there is a wide range.
>
> But I have seen prescription forgeries that were unrelated to
> diversion or abuse in my clinical practice - patients with personality
> disorder or things like that where they were angry that I went on
> vacation, for example, and altered a prescription as a sort of
> impulsive gesture.
>
> So, I think the behaviors themselves don\'t help you necessarily, and
> this is a very, very complicated clinical phenomenon that has to
> sorted out with outside corroboration, urine tox screens, and a whole
> range of other things, but they are not all that common either. The
> behaviors are common, bad outcomes, truly bad outcomes, I think are
> not.
>
> \[Slide.\]
>
> So, what are those bad outcomes? Let\'s say that those behaviors are
> evident in the clinical setting, what might they represent? Sometimes
> they are going to represent abuse by the patient. We don\'t know how
> common that is in our present database.
>
> Addiction, out-and-out addiction is probably very rare in the pain
> population unless people come in with vulnerabilities, but if they are
> not vulnerable people when they are exposed to their opioids, whether
> it\'s oxycodone or any other one, probably they are not going to run
> into difficulties if they don\'t have some pre-existing
> vulnerabilities.
>
> Then, there is chemical coping, which we also don\'t know how
> frequently this happens. What do I mean by \"chemical coping\"? I
> think we all can sort of feel what you think I mean by it, but let me
> just explain that there are aberrant use patterns that we see in the
> clinic that don\'t necessarily qualify as out-and-out compulsive use,
> nor do they qualify as out-of-control use.
>
> They are just on the fringes of what we would consider an opioid
> agreement with the patient, not enough to get them discharged
> necessarily, but, for example, running out early, you know, every
> other prescription, and things of that sort.
>
> These tend to go on in patients who fail to improve or reach
> psychosocial goals that have been set between themselves and their
> clinician at the outset. So, there is a whole range of bad outcomes
> with, as I said earlier, I think the third group probably being more
> common, and when you have a patient who is kind of floundering, not
> using their medicines exactly as prescribed, not making progress
> towards psychosocial goals, and that medicine happens to be a
> controlled substance, this becomes an issue, whereas, it might not be
> if there was not a controlled substance and with quite the same level
> of acuity.
>
> \[Slide.\]
>
> So, which pain patients then are vulnerable to aberrant drug taking?
> Again, very little data, so this is largely unknown. We do know that
> exposure alone to drugs in the context of pain management is probably
> not a risk factor unless, for example, you had someone who had an
> unknown genetic risk or had a genetic risk, let\'s say, who had
> generations of alcoholism in their family, so they decide to be a
> teetotaler, then, they develop a painful condition and they are
> exposed a controlled substance for the first time in a pain management
> setting, and the physician fails to take a good history and doesn\'t
> implement any safeguards. That is probably infrequent, but it is
> feasible that that can happen, that there are people who will get
> exposed, but those are people, as I said, again with vulnerability.
>
> Given that we don\'t have long-term outcome studies in pain
> management, you know, good studies heavily front-loaded for risk
> factors, so then we could see what predicted down the road, all that
> can point you in the direction that everybody around this table is
> well acquainted with, the traditional risk factors for addiction
> including genetic, psychiatric, social, familial, and spiritual risk
> factors.
>
> When we assess our pain patients, there is no question that we have to
> assess them in these areas, because many pain patients have risk
> factors in these areas.
>
> I described the kind of patient who might have a genetic risk factor,
> psychiatric, overwhelming, 80 percent of people with chronic pain have
> a comorbid depression, the social and familiar warping of their life
> circumstances from a year or more of untreated pain gives them risk
> factors often in that area, and many are spiritually bankrupt from
> their struggle to get their life back on track.
>
> So, our patients have risk factors in this area. It behooves us to
> teach our physicians how to assess them.
>
> But one fascinating question that my group is beginning to turn our
> attention to is which ones of these patients then go on to
> self-medicate. If 80 percent of chronic pain patients have a comorbid
> depression, which ones start to use their opioids to medicate that
> depression. We don\'t know the answers to questions like that.
>
> Of those whom self-medicate, how much of that turns into abuse or
> addiction? Again, no answers.
>
> \[Slide.\]
>
> This is a slide just to show you that my group, both, first, when I
> was in Indiana, which was kind of a five-year pit stop between Sloan
> Kettering and Kentucky, when I was in Indiana and subsequently at UK,
> these are some of the studies that we published and we have been
> looking at these attitudes and behaviors in cancer patients and AIDS
> patients, and so on, and I am going to very quickly now walk you
> through the results that I think are illustrative of this problem
> although I will apologize for the methodology.
>
> Someone said earlier that we don\'t even have the methods yet for
> really studying this. Most of our work in collaboration with Russ
> Portenoy and others, and Dr. Katz, over this time has been an
> exploration in trying to figure out what the right methodology is to
> study the problem.
>
> \[Slide.\]
>
> In this particular study, the first one, actually, one of the ones
> down that was on that list, we just completed a NIDA-funded grant to
> look at aberrant drug-taking behavior in cancer and AIDS patients.
>
> I want to point out some very interesting findings from this study to
> you. This not all comers with regards to AIDS patients, these are AIDS
> patients who were specifically chosen because of a history of
> substance abuse.
>
> Both groups had moderate to severe pain. We had 73 patients with AIDS,
> 100 patients with cancer. One hundred percent of the substance abusers
> had reported past or current history of abuse. Some of the cancer
> patients did, mind you, a little bit higher than the national average
> in prevalence in substance abuse for the population especially at that
> age, but substance abuse predisposes to some cancer, so it shouldn\'t
> be all that surprising that it be a little bit higher. There were 101
> men, 72 women. You can see the ethnic breakdown.
>
> \[Slide.\]
>
> We threw the psychosocial medicine cabinet at them, but most
> importantly, from this, we have this aberrant behavior interview that
> Russ Portenoy and Nat Katz and Joyce Lowenson, and several others gave
> us some input to.
>
> \[Slide.\]
>
> With regard to the results, compared to the cancer patients, the
> patients with AIDS were significantly more likely, not surprisingly,
> to be single, male, member of a minority ethnic group, be younger,
> report past or present psychiatric problems, and be inadequately
> medicated for their pain.
>
> So, they have lots of risk factors for aberrant behavior as compared
> to cancer patients.
>
> \[Slide.\]
>
> It is important to look at groups who have a different base rate in
> terms of substance abuse to see if they have a different rate of
> aberrant behavior in the clinical situation, and indeed they did.
>
> The total sample averaged just over three of those behaviors from that
> earlier slide, cancer patients just over one, AIDS patients over six.
> We also broke it down to the less egregious and more egregious
> behaviors, and you can see here that most of them are in the less
> egregious area, but the breakdown, this is a significant difference,
> more common in AIDS patients to have behaviors in this area, probably
> because of their undertreatment.
>
> \[Slide.\]
>
> This just represents what you have already seen, but shows you the
> distribution per percent of the sample for these different numbers of
> behaviors, and over 60 percent of the AIDS sample had five or more of
> those behaviors, whereas, the cancer patients were mostly down at zero
> and one behavior.
>
> \[Slide.\]
>
> I am going to skip ahead here to show you that, indeed, the cancer
> patients, using the PMI, which is a formula developed initially by
> Charlie Cleeland, were much more likely than not to have adequate
> analgesia prescribed to them, whereas, the AIDS patients were much
> less likely to although compared to the numbers that we saw in a study
> that I did with Bill Breitbart at the beginning of the AIDS epidemic
> in New York, these numbers actually are improving and AIDS patients
> appear to be getting prescribed to in better numbers, as well, which
> is nice.
>
> \[Slide.\]
>
> This is probably the most important result of the study that I would
> like to point out to you. When you look at the AIDS patients who had
> adequate and inadequate analgesia according to the PMI, they had
> virtually exactly the same number of aberrant drug-related behaviors,
> and if you compare this ratio, the less severe to the more severe
> behaviors, it is identical in both groups, it is not affected by the
> adequacy of analgesia.
>
> So, what is the take-home message there? If you have two problems, you
> have the problem of pain and substance abuse, your misuse of pain
> medicines is unlikely to be very affected by the adequacy of the
> analgesia prescribed to you.
>
> So, when practitioners assess their patients, if their patients have
> risk factors and problems in both areas, both areas need to be
> addressed. Addressing the pain alone is unlikely to mitigate the risk
> of aberrant behavior.
>
> \[Slide.\]
>
> Just to show you very quickly, this is an assessment tool that Russ
> and Nat and I, and others have had some input into, meant to design a
> chart note to give out to internal medicine and other practitioners
> who treat chronic pain, and it basically help practitioners follow
> people who are on chronic opioids, and it, too, is based on the four
> A\'s model.
>
> \[Slide.\]
>
> I just want to show you, in a study of 388 patients who were given
> opioids for nonmalignant pain, I want to show you the breakdown of
> aberrant behavior in that sample. This is a sample who was getting
> about 57 percent pain relief. Most of these patients were improving in
> their psychosocial functioning. They had a lot of side effects, but
> overwhelmingly rated them as tolerable, and I will show you the data
> on their aberrant behavior. This is a paper that we are just
> completing.
>
> But in this particular study, 55 percent of the sample had no aberrant
> behavior whatsoever. Now, these are not patients separated into
> addition and non-addiction groups. These are just people that come in
> with chronic pain who need opioid therapy. Fifty-five percent of the
> sample had no aberrant behavior whatsoever.
>
> I would again venture a guess, but I suspect if we were looking at
> compliance data with antibiotics or antihypertensives, it would
> probably look similar, and we wouldn\'t be referring to the
> noncompliance as aberrant either. More than likely, just over half had
> absolutely no aberrant behavior.
>
> Forty-six percent of the sample, though, did, but when their clinician
> were asked, only about 10 percent of the individual instances of the
> behavior was it thought to be related to addiction or some serious
> negative outcome.
>
> So, these behaviors are frequent. Remember they come from multiple
> sources, so in the clinical situation, we really need to educate
> people, not with platitudes that there is no addiction and no bad
> outcomes, which I think characterized our earlier rhetoric, but by
> saying to them as many as nearly half of your patients will have a
> behavior that is off the contract somehow, your job, before you can
> react clinically is to sort out the meaning of that behavior.
>
> I will also point out to you that if you look at the big-time repeat
> offenders, remember the AIDS patients, most of them had over five
> behaviors, and those were all addicts. If you look at patients in this
> sample, who had five or more behaviors, it is about 10 percent, which
> is roughly\--and if this result were repeated in a better designed
> epidemiologic outcome study of pain management, that is roughly the
> percentage of patients you would expect to have a problem with opioids
> based on sort of the prevalence of addiction in society at large,
> about 10 percent.
>
> \[Slide.\]
>
> We also did one other study that recently was published in the JNCCN
> where, because Lexington is a referral center for eastern Kentucky,
> which we heard so much about before, we went into our substance abuse
> unit to just characterize the patients who were coming into that
> setting with OxyContin abuse to just try to paint a picture of who
> these patients were.
>
> 195 admissions in a one-year period at the height of the epidemic for
> OxyContin abuse. We got SCID and other medical information on them.
>
> \[Slide.\]
>
> The OxyContin abusers, many of whom were from eastern Kentucky, were
> using on average 180 mg per day. Most of them had a history of other
> substance abuse and non-substance abuse related diagnoses, and
> compared to opioid abusers who were using illicit opioids, they tended
> to be younger, male, and from rural areas.
>
> I think it would be an interesting question that is too afield for
> right now for me to speculate on, on what is it about the sociology of
> rural areas that the epidemic broke out in those areas. I think
> understanding that\--and I would be happy to talk about that later
> because I see a lot of patients from that area\--I think is a key to
> understanding what needs to be done.
>
> \[Slide.\]
>
> Now, this is controversial, but of those 195 admissions to our
> Substance Abuse Units, 60 of those patients were begun on OxyContin
> ostensibly in the context of pain treatment. I have to say
> \"ostensibly\" because we don\'t have a lot of data on their pain
> treatment, we did not have that available.
>
> We are now doing a prospective study of admissions where we are
> getting a lot more data on their pain treatment history, and so on.
> But of the 60 patients who ostensibly began using in the context of
> pain treatment, they were treated mainly by primary care and other
> non-pain experts, they had similar medical and other demographics to
> other OxyContin abusers, and they were equally likely to alter the
> route of administration with some 13 percent of these 60 reporting
> crushing or injecting the tablets to abuse them.
>
> So, it is interesting. I think when I say \"similar medical and
> demographic features,\" I mean to say polysubstance abuse and probably
> several other risk factors that were missed perhaps when those
> patients were started on medicine for their pain.
>
> \[Slide.\]
>
> Back to this issue of who or what should be structured or limited,
> should we be limiting prescribing in general? I really don\'t think
> so, because I don\'t think these outcomes are that common or there is
> that much known about them. I think we need to study them first in the
> pain setting especially before we start doing restrictions that will
> hurt the 55 or much more percent of patients who don\'t misuse their
> medicines in any way.
>
> But I think we can teach doctors to individualize treatment plans
> based on a vulnerability assessment. Bad outcomes in pain management
> are probably not common enough to justify limiting prescribing
> especially, as Art said, when you consider the numbers with 50 million
> pain patients and only 5,000 pain specialists.
>
> Instead, what I have been trying to teach doctors who come to hear me
> speak is that we have to structure individualized treatment plans that
> bring in other means of structuring and limit-setting to patients who
> need that.
>
> There are basically three categories. There are uncomplicated
> patients, there are the middle ground of so-called \"chemical
> copers,\" and then there are abusers with pain. If I were teaching
> doctors, I would say to a primary care doctor, these are patients you
> can treat alone, those you can only treat with help, and those you
> might have to refer out right from the outset.
>
> I think physicians can identify these vulnerabilities and triage
> patients accordingly. I think that is what we need to teach. What I
> find ironic about right now is that we are talking about limiting and
> being concerned about sustained-released delivery system opioids when
> I think some of the problems got set in motion by the fact that rather
> than teaching this, at one time we were teaching that the delivery
> system would do the triaging for us, that sustained-release opioids
> would not be abused because addicts don\'t really like
> sustained-release opioids, and I think that was misguided especially
> when you consider that one can circumvent delivery systems.
>
> \[Slide.\]
>
> Finally, a few hundred conclusions very quickly. Patients of all types
> engage in some ambiguous drug-taking behavior. Substance abuse history
> is associated with an increased number of aberrant behaviors and with
> types of aberrant behaviors.
>
> Provision of adequate analgesia alone is probably not enough to limit
> aberrant behaviors in complicated patients who have a history of drug
> abuse.
>
> Some of the others like needing to base opioid therapy at the outset
> on vulnerability assessments for addiction, and so on, I think I have
> already kind of mentioned, so I will stop there and thank you very
> much for your attention.
>
> DR. KATZ: Questions? Dr. Portenoy.
>
> DR. PORTENOY: Thank you, Steve, I particularly liked that presentation
> because of the number of times you mentioned my name. But I do have a
> question.
>
> Obviously, in trying to sort through the risk:benefit calculation and
> decide about the extent to which a risk management plan should be
> mandatory or not mandatory, to which extent it should be based on
> education versus restrictions, one of the big problems that we have is
> the huge regional differences between the abuse and negative outcomes
> associated with prescription drug diversion, comparing your part of
> the country with my part of the country with respect to OxyContin, for
> example, dramatic difference.
>
> So, I guess the question is from the scientific perspective, are there
> any data that help sort out why that might be the case, do you have
> any speculations about that, and from the research perspective, are
> there potential factors, potential variables that haven\'t been
> assessed yet that maybe need to be assessed to try to sort out why
> Kentucky is a problem?
>
> DR. PASSIK: There is not a lot of research that helps me to understand
> that or answer it. I do see these patients in my clinical practice, so
> I have some speculations, and I am kind of glad that Congressman
> Rogers is gone.
>
> I mean when you look at Eastern Kentucky, I have been there, I have
> worked with the doctors there, I have seen patients in our cancer
> clinic. It is a very isolated area. There tends to be less street
> drugs available there than in other areas. There tend to be less pain
> experts, there tend to be less psychiatric consultants for the primary
> care doctors to utilize.
>
> So, you have a pain revolution that shows up in an area where there is
> not a lot of expertise. You also have a culture that has a tremendous
> amount of chronic pain because of all the coal mining and things that
> go on in that area.
>
> I don\'t mean this in a bad way, I see these patients when they have
> cancer, and I have understood it to be\--and cultures vary with regard
> to this\--it is a bit of a somatizing culture with regard to they
> don\'t come in and say, Steve, I have got, you know, cancer, and I am
> in an existential dilemma. They say my nerves, I have got nerves, you
> know, they experience distress physically. So, when doctors treat that
> distress, I think they tend to treat it medically as opposed to
> psychologically, which fits because there is no resources anyway down
> there.
>
> Then, finally, it is an area of making moonshine and then growing
> marijuana and then selling OxyContin, so there is sort of a cultural
> cottage industry in escapism through pharmaceuticals, if you will.
>
> That is all my speculation. I think, you know, it is very complicated,
> but I think we need to understand the sociology of areas where it is a
> problem and design specific risk management for those areas, and
> education programs for those areas, that may not apply in big city
> settings.
>
> Moreover, then, I also wouldn\'t want to develop one that hurts the
> law-abiding pain patient at the same time.
>
> DR. KATZ: Dr. Dworkin.
>
> DR. DWORKIN: Steve, I have heard you give this talk several times, but
> every time I learn something new, so thank you very much.
>
> My question is, do you have any data or are there any other data
> regarding the question of whether these aberrant drug behaviors are
> more common in patients where the provider is less knowledgeable about
> pain? Are they less common, as we all might imagine in pain
> specialists?
>
> Of course, the point of this question is whether education of
> providers makes a difference. If there are no differences between
> relatively expert providers and relatively naive providers in aberrant
> behaviors in their patients, then, it would suggest to me that maybe
> education doesn\'t make a big difference.
>
> DR. PASSIK: That is a great question, Bob. The answer about data is I
> don\'t believe that there is, and I think the data would be hard to
> interpret anyway because of the fact that the more difficult patients
> end up in the hands of the more knowledgeable practitioners more often
> than not.
>
> But I will say this. I have recently had the occasion to review a
> couple of papers for publication that are probably in the works now,
> doing sort of chart reviews of aberrant behavior in big, busy clinics
> that treat a lot of pain, some pain clinics, others just kind of
> mixed.
>
> One of the things that is associated with aberrant behavior is dose,
> and when you think about that, that says to me that we have been
> teaching this all wrong, because if we were teaching this correctly,
> the clinician who was appropriately monitoring their patient would
> probably reserve the highest, most unorthodox doses for the model
> citizens\--do you know what I am saying\--and that you wouldn\'t be
> escalating the doses in the face of aberrant behavior.
>
> So, what that says to me in terms of the knowledge issue, there may be
> some clinicians who don\'t have much else to offer except to titrate
> up when the patient isn\'t acting right in any way, shape, or form.
>
> Then, the other possibility, too, is that we may have overextended a
> little the pseudo-addiction notion. I think the pseudo-addiction
> notion is very important. It is self-effacing, it takes the burden on
> us to do a better job of pain treatment, and not accuse everyone of
> being an addict in the beginning, but I think that my data question
> sort of, I think to some extent, the validity of pseudo-addiction in
> patients who are actually acting aberrantly in some instances, like in
> the AIDS data.
>
> So, you know, I think we need to teach this correctly, I think there
> is a role for education actually because I think you are probably
> right, you know, in the spirit of your question, that there is a
> difference, and more knowledgeable providers will recognize the
> behaviors and offer alternatives.
>
> I just think that we need to readdress how we have been teaching this.
>
> DR. KATZ: Dr. Strom.
>
> DR. STROM: Two questions. First, in follow-up of Russ\'s question. Do
> you see the same regional variations with alcohol abuse?
>
> DR. PASSIK: The answer is I don\'t know.
>
> DR. KATZ: Does anybody know, anybody at the table know about regional
> variability of alcohol abuse?
>
> \[No response.\]
>
> DR. KATZ: Next question.
>
> DR. STROM: Second, you recommend that instead of using a restrictive
> approach, we should use an educational approach, and we should educate
> docs to base therapy on vulnerability assessments.
>
> Is there any evidence that that leads to decreased aberrant behavior?
>
> DR. PASSIK: No. These models have not really been tested, no. I can
> tell you from clinical experience, though, again, my own, and I have
> been involved in treating a lot of patients who are sort of castoffs
> from other practices for a wide range of offenses, some because they
> had a history of addiction, and some not, that actually, with the
> appropriate limit-setting, if you know how to do that, you have the
> time and the resources to do it, so you have to know which patients
> you can treat and which ones you can\'t, that actually, the experience
> has been rather sanguine, and we have had some very good outcomes.
>
> You know, the whole debate kind of reminds me of years ago, in
> psychology, when they were having this big debate between the
> behaviorist and the personality theorist, and Don Meichenbaum \[ph\],
> who was a big behaviorist, said something like, you know, it doesn\'t
> matter if you are obsessive compulsive or hysterical, both types of
> people stop their car at a red light.
>
> I think if you know how to put the appropriate structure, you can get
> people pain relief. I mean I have had patients where we have doled out
> the medication once a day and gotten them good pain relief, but they
> have had to get medicine on a daily basis because they needed that
> much structure. The average pain practice can\'t do that.
>
> DR. KATZ: Dr. Baxter, did you have a response on that regional
> variability of alcoholism question?
>
> DR. BAXTER: Yes, actually, there is documented data that suggests that
> there is geographical variations. In fact, you will find that there is
> a higher incidence of alcohol use disorders in the broad category, not
> necessarily DSM-IV, a criteria being met in mining and other areas
> that are more geared towards mining. North Central Pennsylvania is one
> of those areas.
>
> DR. KATZ: Dr. Bril.
>
> DR. BRIL: Thank you for a really interesting presentation. I had two
> questions.
>
> My first was I was interested in the difference between the analgesia,
> percentage of analgesia in the AIDS and cancer patients, and I was
> wondering if that was related to the mean dose of whatever opiate
> there was, if there was a standardization against their dose.
>
> DR. PASSIK: The answer to that is no. The PMI doesn\'t take dose into
> account. It simply matches the potency of the analgesia to the
> intensity of the pain.
>
> DR. BRIL: So, we really don\'t know if they were getting a similar
> mean dose of opiate or not.
>
> DR. PASSIK: That\'s correct, and that is an excellent question given
> that those were addicted patients who might very well have needed
> higher doses.
>
> DR. BRIL: My next question is, how does your scheme deal with, say,
> nonresponders? That is about outcome, too. Just people who don\'t get
> analgesia with opiates.
>
> DR. PASSIK: Yes, good question. Well, you know, if you think about the
> four A\'s, there are multiple variations of bad outcomes that you
> could see. I focused on bad outcomes only in that last, the spectrum
> of the last domain there. But you could have a bad outcome, be a
> nonresponder, and everything else would be in order, but you end up
> switching.
>
> You probably would rotate opioids for a while given this heterogeneity
> amongst individuals that Dr. Lipman talked about, but if they truly
> were an opioid nonresponder, you would probably move to another class
> of agents or type of intervention.
>
> DR. KATZ: Dr. Aronson.
>
> DR. ARONSON: Thank you. I appreciated your lecture, and it was the
> first time I heard the four A\'s.
>
> What I took away are several things, but in particular is that there
> is a great deal of sophistication, elegance in identifying and
> understanding the nature of these patients.
>
> We speak of education. We all mention our bias of how we want that to
> work and aren\'t sure that it does, but it is a very broad breadth of
> definition that we probably are all having when we speak of that. So,
> I think we need to go a little bit further.
>
> What constitutes enough in adequate education, is it sending a
> pamphlet in the mail after you fill out a questionnaire and get your
> CME, or is it attending a conference, or is it something that is a
> little bit more measurable on a metric? How would you define adequate
> education that we would even begin to look at?
>
> DR. PASSIK: That\'s an excellent question and I am not sure that I
> have the ultimate answer, but I think that people who prescribe pain
> medicines need to be knowledgeable in the complications of prescribing
> those medications including a certain level of expertise in addiction
> medicine depending on the population they treat, or at least addiction
> medicine as it is applied to the pain management setting.
>
> You know, different places have taken this on in different ways. In
> California, they mandated pain education CME credits that physicians
> have to get. I don\'t know that that is the correct approach, but I
> mean I think at the very least\--and it\'s hard for me to gauge what
> the effect of this would be because, as I said earlier, I think the
> rhetoric and the excitement around the revolution in pain management
> tended to play down these issues.
>
> So, it is not as if we have spent the last many years as this has been
> going on teaching about the negative outcomes and what to do and how
> to recognize it. There has been an effort. Some of the pharmaceutical
> companies have been involved in that effort to do that up until now.
>
> So, it is hard for me to answer that question in specifics, but I
> think we haven\'t really begun the process of teaching about bad
> outcomes really in opioid therapy.
>
> DR. KATZ: I am going to ask one last question before we move on in our
> schedule.
>
> Steve, it sounds like if I heard you correctly, that there really are
> no validated criteria in the setting of managing chronic pain to
> diagnose addiction or any of the other negative outcomes that you
> discussed. Yet, it seemed like your presentation suggested that those
> are important complications or concomitants that occur in some
> percentage of people as part of opioid therapy.
>
> Do you feel that validation of diagnostic criteria for diagnosing
> these complications is essential in the safe and effective use of
> opioids for managing of chronic pain?
>
> DR. PASSIK: Yes, I do, I think we need that. I think we also need
> validated tools. I would not refer to the PADT as validated in any
> way, shape, or form. We kind of road-tested it, but we did not
> validate it.
>
> We tested it our for acceptability, but it is yet to be a validated
> tool, so we don\'t have validated assessment tools for studying this
> problem. We don\'t have validated criteria. Some of us in the pain
> field, a lot of the psychologists, psychiatrists who do pain work have
> kind of toyed with the idea, and then Steve King from New York
> actually went to the APA, American Psychiatric Association, to try to
> get them interested in beginning the field trials to develop some
> criteria, and as far as I know, they didn\'t bite.
>
> DR. KATZ: Thanks very much.
>
> I have got good news and bad news about our schedule, mostly bad. The
> bad news, first of all, we are way beyond schedule, as I think
> everybody who has a schedule knows. The good news is that Dr. Willis
> has agreed to give her presentation, which had been scheduled for
> 11:45, after lunch. I can also see that people are getting antsy.
>
> So, what I would like to do now is take a two- or three-minute leg
> stretching break, so don\'t go too far, then, we have three
> presentations from SAMHSA, that are scheduled to go for almost an
> hour, so I would like to try to get those presentations started after
> about three minutes when people have had a chance to stretch, then, we
> ought to be able to break for lunch at around 12:30, 12:35.
>
> We will begin again at 1:15 with Dr. Willis\' presentation and then
> have the open public hearing between 1:45 and 2:00. So, I will see you
> all back again in about three minutes.
>
> \[Break.\]
>
> DR. KATZ: We will now have three presentations from SAMHSA, our first
> presentation from Mr. Gfroerer will be Nonmedical Use of Pain
> Relievers: Data from the National Survey on Drug Use and Health.
>
> **Nonmedical Use of Pain Relievers: Data from**
>
> **The National Survey on Drug Use and Health**
>
> MR. GFROERER: Joe Gfroerer is my name. I am the director of the
> division that runs the National Survey on Drug Use and Health. If some
> of you have never heard of it, that is because the survey was renamed
> last year. It used to be called the National Household Survey on Drug
> Abuse. It has been conducted for about 30 years now.
>
> \[Slide.\]
>
> Just to give you a little background on the design of the survey,
> actually, it has been about the same design over the entire 30-year
> period with a few changes now and them. It covers the entire country,
> it is representative nationally and also within each state, the sample
> is large enough and designed, so that we can get estimates within
> every state and the District of Columbia.
>
> The population coverage is the civilian, noninstitutionalized
> population, age 12 and older. The data are collected using an
> anonymous face-to-face interview with computer-assisted interviewing.
>
> Most of the questions, in fact, all the questions on drug use and
> other sensitive behaviors are done with self-administration where the
> respondent keys in the responses on the computer.
>
> Questions come up on the screen and also in headphones, so that they
> can listen, and this is to promote privacy and encourage honest
> reporting.
>
> In 2002, we had 68,000 respondents.
>
> \[Slide.\]
>
> Besides the name change, there were some other changes that occurred
> in the survey, most importantly was that we started paying incentives
> to respondents. Every person who participates in the survey is given
> an incentive payment. Unexpectedly, this turned out to actually affect
> the reporting of the various behaviors on the survey, so the 2002 data
> represents a new baseline for the estimates that we produce. These
> estimates from the 2002 survey are not comparable for trend purposes
> to the earlier surveys.
>
> \[Slide.\]
>
> The nonmedical prescription drug use data that we collect is based on
> this definition. Of course, the survey focuses mainly on marijuana,
> well, it focuses on all substances, marijuana, cocaine, heroin, and
> also tobacco and alcohol, but there are also a series of questions on
> prescription type drugs using this definition, prescription drug that
> is not prescribed for you, or you took the drug only for the
> experience or feeling it caused.
>
> This is within the context of the entire survey asking about all the
> other illicit drugs. So, we are not picking up legitimate use, and we
> do exclude over-the-counter misuse, as well as use.
>
> \[Slide.\]
>
> The way the data are collected it we focus on major categories of
> drugs, and what we have defined as pain relievers looks like this. It
> is primarily opiates, but the way we ask the questions is that we use
> a pillcard like this with pictures of really the most prevalent pain
> relievers, and use this as a memory jog for the respondent.
>
> The main purpose is to initially identify if the have ever used any of
> these substances, and then if they have used at least one. Then, we go
> into more detailed questions about current use and frequency of use
> and problems associated with the group pain reliever, so we only get,
> for these specific drugs shown on this pillcard, we only get whether
> they have ever used that drug.
>
> The way it is done here, it is also important to note that above the
> red line here on the pillcard, you have these three major categories,
> and there is a question for each of those - did you ever use Darvocet,
> Darvon, or Tylenol with codeine? Yes/No. So, that is asked for those
> three, and those three cover a large percentage of all the pain
> reliever abuse that we pick up.
>
> Then, there is another question that asks if they have used any of the
> other pills shown on the card below the red line, and then they just
> check off which ones they have used, so we don\'t go through each of
> these specific drugs, all 21 drugs, and ask about whether they have
> used them.
>
> So, what we have, again, this is used as a memory jog, it is not
> intended to provide the most precise estimates for the use of each of
> these substances. We know that this method of asking about some of
> these drugs at the bottom of the chart is going to be giving us
> conservative estimates because there will be some drugs that won\'t be
> reported.
>
> \[Slide.\]
>
> Here is the estimate of lifetime use that we get from using that
> pillcard. You can see the top three are those three above the red
> line, the Darvocet, Darvon, Tylenol with 18.9 million lifetime users,
> and you can see the other drugs - codeine, hydrocodone, demerol,
> morphine, OxyContin at 1.9 million, Dilaudid at 1.1 million.
>
> \[Slide.\]
>
> Here is what the pain reliever data looked like when we put all those
> lifetime measures together and asked the more specific questions about
> use of pain relievers in general. Overall, about 29.6 million, which
> is 12.6 percent of the population 12 and older, have ever used any of
> those pain relievers nonmedically, and 10.9 million was 4.7 percent
> had used in the past year, and 4.4 million in the past month.
>
> Then, we also have a series of questions that try to get at DSM for
> dependence or abuse. For anybody who has used any of the pain
> relievers nonmedically within the past year, they go through a series
> of questions asking about the DSM criteria, and then we classify
> people as to whether they are dependent or abuse.
>
> Here we have an estimate of 1.5 million, which is 0.6 percent of the
> population.
>
> \[Slide.\]
>
> Just to put that in context, here is what the dependence or abuse
> estimates looked like for all the substances we asked about, of course
> excluding alcohol, which would be way off the chart, but marijuana is
> at 4 million, 4.2 million, and pain relievers and cocaine are about at
> the same level, at about 1 1/2 million, higher than tranquilizers,
> stimulants, hallucinogens, heroin, inhalants, and sedatives.
>
> \[Slide.\]
>
> Now, the trends, even though I told you we can\'t compare to the
> earlier data, what we have done here is we have constructed trends
> just from the new data from the 2002 survey by using the responses to
> the questions on age at first use, so if we know that somebody has
> first used 10 years ago, you can back date when they were a lifetime
> user and correct for their age.
>
> So, we construct these trends based on that and it shows substantial
> increases in nonmedical pain reliever use. This is looking at the 12
> to 17 age group and the 18 to 25 age group.
>
> \[Slide.\]
>
> Also, looking at some of the specific drugs, we can see the OxyContin
> trend here, which we saw up through the 2001 survey, basically
> doubling each year from around 200,000 up to 400,000 and then up to
> about a million in 2001. I wanted to show what the 2002 data looked
> like.
>
> I made it a different color with a different label and put a line down
> the middle just to make the point that these are not really
> comparable, but on the other hand, none of the comparisons we have
> made, none of the effects of the change in the survey were this large,
> so I think it is safe to say that the estimate is higher or the number
> of users of OxyContin is higher in 2002 than 2001 although it may not
> be at this level doubling.
>
> \[Slide.\]
>
> Another way we can look at the trends besides looking at lifetime use
> is to look at how many new users each year, how many people first
> tried pain relievers for the first time in that year, and here is what
> the trend looks like there.
>
> There is a small dip at the end there of that curve which is not
> statistically significant, but basically, it does show that not only
> was there an increase in initiation of pain reliever misuse in the
> \'90s, in the late \'90s, but it is still at a high level of over 2
> million new users each year.
>
> \[Slide.\]
>
> Now, one thing we can do to look at what the\--even though we only
> have the lifetime use of OxyContin\--if we want to see what effect,
> how that trend in OxyContin misuse is related to the overall pain
> reliever trend, and is it driving that trend, well, here, we are
> looking at the recent new initiates to pain reliever abuse.
>
> In other words, on this chart here, if you look at the last three data
> points, those are the recent new users, and it\'s about 7 million
> people. So, we take that population and look at what other drugs they
> have used, and you see that most of them, 75 percent have used
> marijuana, 46 percent hallucinogens, 32 percent cocaine, 3 percent
> heroin. Only 9 percent ever used OxyContin, so it doesn\'t look like,
> from those data, that the increase in pain reliever misuse is being
> driven by OxyContin use.
>
> \[Slide.\]
>
> Another way to look at it would be to look at the 1.9 million
> OxyContin users, nonmedical users, and just see what other drugs have
> they used, and you see 98 percent have used some other pain reliever
> nonmedically, 98 percent have used marijuana, 89 percent
> hallucinogens, and cocaine and heroin, as well. So, clearly, the
> people who are using OxyContin are coming from a group that are
> already using other illicit drugs.
>
> \[Slide.\]
>
> This shows that first group in more detail. Again, this is the
> lifetime OxyContin users looking at what other pain relievers they
> use, and it\'s across the board, 80 percent with the Vicodin, Lortab,
> Lorcet, and high percentages of all the other pain relievers from that
> pillcard.
>
> \[Slide.\]
>
> These next few slides take a look at the demographics of the OxyContin
> users, the lifetime OxyContin users, comparing them to the
> demographics of overall pain reliever abusers. This would be the
> population with dependence or abuse on pain relievers on the left
> compared to the OxyContin users, just to look at the shape of the
> curve and whether there is a different population with OxyContin use.
>
> This is certainly a similar pattern here with the younger age groups
> having the higher rates, but among the OxyContin users, that
> 18-to-25-year-old group really dominates much more than it does for
> the pain reliever dependence and abuse.
>
> \[Slide.\]
>
> Looking at it by gender, there is really no difference in the rate of
> dependence or abuse on pain relievers between males and females, but
> OxyContin users are more likely to be male, 1 percent versus 0.6
> percent.
>
> \[Slide.\]
>
> This looks at race/ethnicity and you can see that the OxyContin users
> are much more likely to be white and much less likely to be black or
> African-American or Hispanic.
>
> \[Slide.\]
>
> This breaks it out by\--it is not really rural areas, but you are
> looking at, in the blue bar there, the nonmetropolitan areas, we
> don\'t have enough data to break it out into true rural areas, but it
> does show that the rates are about the same in the nonmetropolitan and
> the large metropolitan areas, but it is the small metropolitan areas,
> those would be metropolitan areas with less than a million population
> that have the highest rate of dependence or abuse on pain relievers,
> as well as lifetime OxyContin nonmedical use.
>
> \[Slide.\]
>
> Finally, this slide looks at the dependence or abuse on any pain
> reliever depending on whether the person has ever used OxyContin or
> not, and also Dilaudid at the bottom. You can see that of the pain
> reliever users who have used OxyContin, 20 percent have dependence or
> abuse, and only 4 percent of the other pain reliever users have
> dependence or abuse.
>
> Similarly, for Dilaudid, the Dilaudid users are more likely to be
> dependent or abusing than users of pain relievers that did not use the
> Dilaudid.
>
> \[Slide.\]
>
> Just to summarize the conclusions of these data, first of all, there
> is significant increases in nonmedical use of pain relievers and
> OxyContin in particular. The nonmedical OxyContin users are primarily
> coming from a population who are already abusing other drugs, and the
> OxyContin and Dilaudid users are more likely to have dependence or
> abuse on pain relievers than other nonmedical pain reliever users.
>
> That\'s it. Thanks. I will take questions, I guess.
>
> DR. KATZ: Actually, I think it would be better to hold questions until
> after all three SAMHSA presentations, so if I could ask people to just
> jot down their questions and save them for the end.
>
> Thanks. Hopefully, you won\'t go too far and we can hear from you.
>
> Our next speaker is Deborah Trunzo, who is the team leader of the
> Office of Applied Sciences at SAMHSA, who will be presenting Data on
> Treatment Admissions for Opiate Abuse.
>
> **Data on Treatment Admissions for Opiate Abuse**
>
> MS. TRUNZO: I am going to be talking about data from the Treatment
> Episode Data Set, specifically, treatment admissions for the abuse of
> opiate analgesics.
>
> \[Slide.\]
>
> The Treatment Episode Data Set, or TEDS as we call it, consists of
> client-level information on admissions to substance abuse treatment.
> This is information that is routinely collected by states by monitor
> their individual substance abuse treatment systems. So, as a
> consequence, TEDS includes data primarily from treatment facilities
> that receive public funds.
>
> TEDS is a very large data set. We get about 1.7 million admission
> records annually from the states, and I should add that at any given
> time, virtually all the states are participating in TEDS.
>
> Selected data items from the individual state data systems are
> converted to a standardized format consistent across the states, and
> then these standardized data are what make up TEDS.
>
> \[Slide.\]
>
> The TEDS data elements include demographic variables, such as age,
> gender, race, and ethnicity, but the heart of TEDS is formed by the
> data elements on drug use. For each admission, the primary, secondary,
> and tertiary drugs of abuse are identified along with route of
> administration, frequency of use at admission, and the age at which
> the client first used each drug.
>
> The treatment variables in TEDS include the type of treatment service
> to which the client is admitted, whether methadone is planned as a
> part of the treatment, the number of prior treatment episodes, and
> source of referral.
>
> \[Slide.\]
>
> TEDS is sort of a strange beast and has quite a number of features and
> limitations that are important to understand before getting into the
> actual data.
>
> First of all, it is important to be aware that TEDS is an
> admission-based system, it does not count individuals, so, for
> example, a person admitted to treatment twice within a calendar year
> would count as two admissions, not as one.
>
> Despite its size, TEDS does not include all admissions to treatment.
> Because the data comes from state systems, admissions to
> federally-owned facilities, such as VA facilities, are not included,
> and also, as a rule, admissions to private for-profit facilities are
> not included.
>
> So, in terms of absolute numbers, TEDS underestimates the scope of the
> problem. We estimate that TEDS probably covers about 80 percent of the
> nation\'s substance abuse treatment admissions.
>
> Another important factor to keep in mind is that TEDS reports on the
> top three drugs of abuse at time of admission. It does not include all
> the drugs that the client may have abused prior to admission.
>
> Also, substances of abuse are reported to TEDS in generic categories
> or classes. My particular this morning or this afternoon, I should
> say, will be on a group of drugs in TEDS classified as \"Other\"
> opiates. By that, I mean other than heroin and other than
> nonprescription methadone.
>
> This category, by elimination, consists of opiate analgesics. TEDS has
> some very limited data on specific drug within this group, but even
> so, TEDS is not able to identify specific formulations or brand names.
>
> \[Slide.\]
>
> I think for the purposes here today, it is important to realize that
> TEDS is not an early warning system, in fact, it is the opposite.
> Typically, there is a lag of some years between first use of a
> substance and admission to treatment for abuse or addiction of that
> substance.
>
> Unfortunately, there is also a considerable time lag between treatment
> admission and when we receive the admission data records from the
> states. This delays the release of TEDS data at the national level, so
> much of the data that I will be showing you in a minute is for the
> year 2000.
>
> However, having said all this, TEDS data does have predictive value.
> The nature of addiction is a constant, so knowledge of past patterns
> of abuse that have led someone into treatment can be useful for
> assessing future risk.
>
> \[Slide.\]
>
> Now, for some of the data. As indicated by the small red sliver on
> this pie, admissions to treatment for primary abuse of opiate
> analgesics made up a very small proportion of the 1.7 million
> admissions to treatment reported to TEDS in the year 2000, but in
> terms of absolute numbers, even 2 percent represents a significant
> problem. This is around 30,000 admissions.
>
> \[Slide.\]
>
> In 2000, there were about 50,000 admissions to treatment where the
> primary, secondary, or tertiary substance of abuse was an opiate
> analgesic. For half of these admissions, narcotic analgesics were the
> primary substance of abuse. The other half represented dual
> addictions, such as abuse of opiate analgesics in addition to abuse of
> another substance. Most often this was alcohol or heroin.
>
> \[Slide.\]
>
> TEDS has been producing data since 1992, which allows us to look at
> trends. As shown here, the number of treatment admissions in which
> opiate analgesics were involved was relatively stable between 1992 and
> 1997, but this increased sharply in 1998, 1999, and 2000. So, the
> question is what is behind this dramatic increase.
>
> Unfortunately, TEDS cannot answer this question conclusively, but the
> beginning of the sharp rise does follow the introduction of OxyContin.
> This suggests that we may be seeing the early part of the wave of
> OxyContin addicts. If this is the case, we would expect the increase
> to continue as the wave has some more time to build.
>
> \[Slide.\]
>
> The data appear to bear this out. Although national data are not yet
> available for 2001 and 2002, at this time, we do have preliminary data
> from some states.
>
> Five states were responsible for 40 percent of all admissions
> involving opiate analgesics in 1999 and 2000. These states are
> California, Florida, Massachusetts, New York, and Pennsylvania. These
> states have reported their preliminary data for 2001 and 2002. In each
> of these states, the dramatic increase in the number of opiate
> analgesic admissions continues into 2001 and 2002.
>
> \[Slide.\]
>
> The five states in the previous slide accounted for large numbers of
> admissions, but there may be other states where admissions for opiate
> analgesics are occurring at an even higher rate.
>
> This map shows the rate of admissions involving these drugs by state
> for the year 1992. This year was used to set benchmarks for comparison
> with subsequent years.
>
> The five red states represent the top 10 percent of reporting states\'
> rates in 1992. In these states, admissions for opiate analgesics were
> at least 24 per 100,000 population.
>
> The brown states have rates in the top 11 to 25 percent, and the
> yellow states have rates in the top 26 to 50 percent. The pale yellow
> states are those in which the admission rate was below the median for
> all states combined.
>
> \[Slide.\]
>
> By 1997, rates had increased in a number of states. There are now 11
> states with admission rates of at least 24 per 100,000 population.
>
> \[Slide.\]
>
> By 2000, 22 states had opiate analgesic admission rates of at least 24
> per 100,000. Rates were particularly high in the New England States
> ranging from 75 per 100,000 in Connecticut to 150 per 100,000 in
> Maine.
>
> \[Slide.\]
>
> The increase in admissions involving opiate analgesics between 1992
> and 2000 was much larger than could be accounted for by an overall
> increase in treatment admissions. In TEDS, the total number of
> treatment admissions increased by 15 percent during these years.
>
> In that same period, admissions for primary heroin abuse increased by
> 64 percent. Admissions for primary abuse of opiate analgesics
> increased by 181 percent, and the number of admissions involving any
> primary, secondary, or tertiary abuse of these drugs increased by 143
> percent.
>
> \[Slide.\]
>
> A group of 10 states collect data on the specific opiate analgesics
> responsible for treatment admissions. In the three years from 1997 to
> 2000, treatment admissions involving narcotic analgesics increased by
> 49 percent. Specific drugs had increases that were much higher, 391
> percent for oxycodone, 257 percent for propoxyphene, and 172 percent
> for hydromorphone.
>
> \[Slide.\]
>
> The characteristics for admissions of abuse of narcotic analgesics did
> not change much between 1992 and 2000. Just over half were male, and
> over 80 percent were white. About three-quarters were 30 years old or
> more. Referral to treatment through the criminal justice system was
> relatively rare as most admissions were self-referred.
>
> The major change between 1992 and 2000 was the substantial increase in
> the proportion of new users of opiate analgesics, and we define new
> users as those entering treatment within three years of first use. The
> proportion of new users increased from 27 percent in 1992 to 41
> percent in 2000.
>
> \[Slide.\]
>
> This slide compares for the year 2000, all admissions involving opiate
> analgesics and new users of opiate analgesics. Their demographic
> characteristics are similar with the exception of age. The new users
> are younger, 12 percent are under the age of 20, and 40 percent are
> under the age of 30.
>
> \[Slide.\]
>
> As mentioned before, in 2002, treatment admissions involving opiate
> analgesics were overwhelmingly white.
>
> \[Slide.\]
>
> In this slide, 1997 admissions are depicted by the green line, and
> 2000 admissions by the red line. The number of admissions involving
> opiate analgesics increased for all ages during the three-year period,
> but the largest increase was among young people.
>
> \[Slide.\]
>
> This slide shows the same information by sex from 1997 to 2000. There
> were increased numbers of both male and female admissions involving
> opiate analgesics. The increase was especially pronounced among young
> men.
>
> \[Slide.\]
>
> Finally, this slide shows the trend in median duration of use before
> first treatment in the five large states that I had mentioned earlier,
> that is, California, Florida, Massachusetts, New York, and
> Pennsylvania.
>
> Between 1997 and 2002, the time between first use of opiate analgesics
> and admission to treatment for abuse of these drugs had declined by
> half. In 1997, the median duration of use before treatment was eight
> years. By 2001, it was only four years.
>
> Contrast this with earlier years in which the median time before
> treatment was 10 years. Again, the question is raised what are the
> causes of this shift in behavior amongst abusers of opiate analgesics,
> and again, a plausible hypothesis, given other evidence, is that
> OxyContin may be a factor.
>
> That is all that I have to present this morning. Our 2001 report with
> national data will be coming out shortly, and I encourage you all to
> check out the SAMHSA web site, click on Statistics and Data, and you
> will find more information on TEDS and the specific states that are
> involved.
>
> Thank you.
>
> DR. KATZ: Thank you very much.
>
> Once again, we will just hang onto your questions until the end of the
> next presentation, which will be by Dr. Judy Ball, who is the team
> leader of the Office of Applied Sciences at SAMHSA who will be
> presenting Opiate Abuse Data for us.
>
> **Opiate Abuse Data**
>
> DR. BALL: I am not going to go through much of the methodological
> detail that was provided in your briefing book in the interests of
> time. I am, however, going to talk today about immediate- and
> sustained-release opioid analgesics as shown in the DAWN data.
>
> \[Slide.\]
>
> All of the findings that I am presenting today will come from the
> national probability sample of hospitals. In 2002, we had 437
> hospitals that participated in DAWN. It\'s a representative sample of
> hospitals for the 48 states. We also collect data on drug abuse
> related deaths that are reviewed by medical examiners and coroners.
> That is not a national database, and I will not be presenting any of
> that information today.
>
> \[Slide.\]
>
> DAWN cases, it is important to remember that a DAWN case is a patient
> who is between the age of 6 and 97, who was treated in the emergency
> department. The visit is related to drug abuse, and that is defined
> very narrowly as the patient intended to use the drug for dependence,
> or psychic effects, or for suicide attempt or gesture.
>
> During the period of the data I am showing you today, DAWN did not
> collect anything that did not meet this narrow definition of drug
> abuse.
>
> \[Slide.\]
>
> The drug detail in DAWN is quite varied. We collect data on illicit
> prescription and over-the-counter drugs, but the specificity of that
> drug information is dependent on what is contained in the medical
> record. So, sometimes we get brand names, sometimes we get chemical
> names, sometimes we get generic, sometimes we only get classes of
> drugs, and that is a particular challenge in looking at the opiates
> for this presentation.
>
> The drug mention is simply a unit of measurement for individual drug.
> Most visits involve more than one drug, 1.8 drugs on average. So, each
> individual report of a drug is referred to as a mention.
>
> \[Slide.\]
>
> To put the opiate data into context, this chart compares estimates for
> 1994 and 2002. The 2002 bar is the pink one, 1994 is the gold one.
> This shows that the opiates, the top set of bars there, other than
> heroin, grew 2.7 times over this nine-year period. Marijuana, the
> third set down, grew nearly 3 times, but cocaine, heroin, and the
> benzodiazepines grew less than 50 percent over this time period.
>
> The bottom line is that by 2002, the opioids were as frequent in
> emergency department visits related to drug abuse as heroin or
> marijuana, but they were less frequent than cocaine.
>
> \[Slide.\]
>
> This shows you a breakdown of the opiates and opioids in DAWN.
> Thirty-five percent of the mentions are due to an unnamed ingredient.
> Virtually all of these are reported to DAWN simply as opiates. It is
> very likely that this is information that is coming from laboratory
> tests that may not have had confirmatory testing.
>
> The four named opiates that we are focusing on today, hydrocodone,
> oxycodone, morphine, and fentanyl make up about 44 percent of mentions
> of opioids, and the other 21 percent come from the various others,
> codeine, and so forth.
>
> \[Slide.\]
>
> Now, for this analysis, we can break the various opioids down into
> those that have immediate release type, sustained release types, and,
> of course, in DAWN, we always have to contend with the types that are
> unspecified.
>
> So, for the unnamed, for example, they would always be unspecified.
> Hydrocodone or hydromorphone, because they only occur in immediate
> release products, can all be classified as immediate release, but
> fentanyl, morphine, and oxycodone can be divided between immediate
> release products, sustained release products, and those products that
> were reported to us without specifying the formulation.
>
> \[Slide.\]
>
> So, to look at trends for each of these groups, we will first look at
> the unnamed opiates, which are, in fact, the most frequently reported
> opiate, but we can\'t ignore them because they are the most frequent.
>
> Over the nine years, there was 400 percent increase, and we have seen
> a one-year increase from 2001 to 2002 of 31 percent.
>
> \[Slide.\]
>
> For hydrocodone, which is available only in immediate release forms,
> it is the second most frequently reported opiate in DAWN. In 2002,
> there were over 25,000 mentions, and the nine-year increase in
> hydrocodone was 170 percent. The recent increases from 2001 to 2002
> are fairly moderate at 17 percent. The two-year increase from 2000 to
> 2001 was 25 percent.
>
> \[Slide.\]
>
> Hydromorphone. These numbers are much smaller. Where we were talking
> in the tens of thousands previously, now we are talking in the
> individual thousands. You will see that for hydromorphone, I do not
> have an estimate here for 2000, 2001, or 2002.
>
> The reason is that the relative standard errors on these
> estimates\--don\'t forget these are all estimates that are produced
> from sample data\--so there is sampling error surrounding all of the
> estimates.
>
> Estimates for these three years for hydromorphone had relative
> standard errors that exceeded 50 percent. That, in essence, means that
> the estimate may not be significantly different than zero, so we do
> not report them because we don\'t trust them.
>
> The other years that you see here, there is still a fair amount of
> variation. Only two years, 1995 and 1996, had relative standard errors
> below 30 percent, so there really isn\'t a whole lot that we can
> conclude from the hydromorphone estimates.
>
> \[Slide.\]
>
> Fentanyl. It does have an immediate and a sustained release product,
> but the numbers in DAWN are such that if we break them apart, we run
> into precision problems, so they are all combined here, all different
> types.
>
> What we see with fentanyl is an interesting pattern. From 1999 to
> 2001, that two-year period, we saw more than a doubling in mentions,
> and then in the last two years, 2001 to 2002, we see another more than
> doubling, but the numbers here are so very small, the estimate in 2002
> is 1,506 mentions. It is really quite tiny.
>
> \[Slide.\]
>
> For morphine, again, there is an immediate release, there is a
> sustained release, but when we break them apart, the estimates aren\'t
> precise enough to present, so this is all types.
>
> Morphine has been behaving quite differently than the other opiates in
> emergency department mentions. We do see a significant increase of 126
> percent. That is more than doubling from 1996 to 1998, a 71 percent
> increase from 1997 to 1999, but in recent years, although the bars
> look like they are different heights, those are not significant
> differences. Those variations that you see there are within the margin
> of error.
>
> \[Slide.\]
>
> Now, for oxycodone, the numbers are large enough that we can, in fact,
> split them into immediate release, sustained release types, and types
> unspecified, and this is the first set of bars for the types that are
> unspecified.
>
> The numbers are fairly low. I was actually surprised when I looked at
> this at how low they were. You don\'t see a bar in 1995 because the
> estimate had a relative standard error of greater than 50 percent, but
> the other years, the estimates are within reasonable ranges.
>
> We do not see an increase when we look at the last two years, from
> 2000 to 2002, or 2001 to 2002. The only significant increase we see in
> these actually occurs between 1996 and 1998.
>
> \[Slide.\]
>
> For the immediate-release types of oxycodone, the numbers here are
> considerably higher than the unspecified ones. We do see a significant
> increase from 1996 to 1998 of about 37 percent, another significant
> increase from 1999 to 2001 of 59 percent, but the estimates for 2000,
> 2001, and 2002 are essentially stable, there are no significant
> differences there, and this is all of the immediate-release types of
> oxycodone.
>
> \[Slide.\]
>
> For sustained-release types, this is largely OxyContin, the OxyContin
> was first approved I believe in 1995. We saw the first mention in DAWN
> was actually in 1997, but the numbers were so small, you can\'t see
> them. Since then, the increases have been quite dramatic.
>
> By 2002, we see over 14,000 mentions of sustained-release oxycodone in
> DAWN nationally, and the one-year increase was 41 percent. The
> two-year increase, though, is quite shocking because it\'s over 400
> percent, but we are also talking about starting out with numbers that
> are very small. When you are working with small numbers, you get
> really big percentage increases very easily.
>
> \[Slide.\]
>
> So, if we put the three types together for oxycodone, the trend looks
> like this. Here again, the sustained-release is the yellow, the
> intermediate-release is the pink, the unspecified types, the blue.
>
> The nine-year increase overall is about 450 percent. The one-year
> increase actually here between 2001 and 2002 is not significantly
> different, and it is because of the modulating effects of the
> immediate-release here, but we do see a doubling in mentions over the
> past two years, between 2000 and 2002.
>
> The total number of mentions in 2002 for oxycodone here is over 22,000
> mentions, and since 1998, we have seen a doubling every two years in
> those mentions.
>
> \[Slide.\]
>
> This is going to show you the proportions across time as the
> sustained-release versions of oxycodone have become more prominent. It
> starts out at zero in 1997 and goes to 63 percent of all the oxycodone
> mentions by 2002.
>
> \[Slide.\]
>
> My colleagues have talked before about the issue of multiple drug
> abuse, and we certainly see the same in DAWN. I took all of the DAWN
> episodes that involved a mention of the four major drugs that we are
> looking at here - fentanyl, hydrocodone, morphine, and oxycodone.
>
> I didn\'t do the hydromorphones because of the precision problem, and
> looked at these in terms of visits, not in mentions, and then looked
> within the visit that involved one of these index drugs of what other
> drugs were there.
>
> The findings were quite interesting. We find that the fentanyl numbers
> are a little different, but we see quite consistent patterns for
> hydrocodone, morphine, and oxycodone. More than two out of three of
> the visits involving one of these drugs also involved other drugs.
>
> A large share of them, about 4 out of 10, involved a major substance
> of abuse, and \"major substance of abuse\" in DAWN lingo are the
> standard alcohol, cocaine, heroin, marijuana, amphetamines,
> methamphetamines, and the less frequent drugs of abuse, such as the
> club drugs Ecstasy, JHB, and so forth.
>
> We also see that there is a moderate share, we see here 13 to 26
> percent of visits involving these drugs also involve a benzodiazepine,
> and then when I actually looked at these drugs and then looked to see
> if there was more than one opiate in the particular visit, I find a
> surprising number, from 14 percent to 27 percent of the visits
> involving these drugs also involve another opiate.
>
> So, the idea of the polysubstance abuse that comes out in each of
> these data sets, I think is really quite remarkable and confirmatory.
>
> \[Slide.\]
>
> Let me remind you again the limitations of the DAWN data that we are
> looking at here. These are reportable cases of drug abuse based on the
> patient\'s intent as documented in the medical record. Patients are
> never interviewed, so this information has to be gleaned from a
> retrospective review of charts.
>
> We do have variable reporting of nonspecific terms, and it is possible
> that a chart could indicate that a patient took OxyContin, and they
> took some other form of oxycodone. How many times have you heard
> people misuse the two terms? That is possible, and it is not something
> that we can quantify.
>
> It is also not possible to distinguish from these data, diversion
> versus abuse of these drugs from people who have legitimate
> prescriptions, it is simply not possible, and for the period of time
> that these data cover, we actually collected, except for knowing that
> the person was in the emergency department for some treatment, we
> don\'t have any information about the health condition that brought
> them there.
>
> I am happy to say that starting in 2003, we are correcting that and
> making headway on many of these other limitations, as well.
>
> Thank you. I will be happy to take our questions, as will my
> colleagues.
>
> DR. KATZ: Thank you, Dr. Ball.
>
> Let\'s go ahead and take questions. Dr. Shafer, you had one from
> before. Do you still have a question?
>
> DR. SHAFER: This is a question for Ms. Trunzo. You showed us data that
> use of narcotic analgesics from 1997 to 2000 had gone up 49 percent,
> and then specifically, cocaine had gone up 71 percent, hydromorphone
> 172, oxycodone 391 percent, but I didn\'t see anything going down, and
> all of the individual components have gone up much more than 49
> percent.
>
> So, my question is what went down during that period of time?
>
> MS. TRUNZO: That is a fair enough question. There is a large component
> of \"Other,\" other opiates that we can\'t sort out, we don\'t know
> what has gone into that pot, but amongst the ones, the specific ones
> that are identified, they had gone up, the oxycodone and hydromorphone
> and propoxyphene had gone up the amounts that I had said.
>
> But in terms of numbers, the ones in the \"Other\" category far
> outnumber the ones that we can\'t identify in the \"Other\" category
> are by far in the largest pot, so the average then is brought down to
> 49 percent overall.
>
> DR. SHAFER: So, some of the increase is then just simply reclassifying
> \"Other\" into these other categories.
>
> MS. TRUNZO: Yes, right, it is a small portion of the total \"Other.\"
>
> DR. KATZ: Dr. Strom.
>
> DR. STROM: I think between what we heard in the first of the
> presentations and what we heard before from the Office of
> Pharmacoepidemiology have the answers to the question I asked earlier,
> but I want to nail that down to be sure.
>
> If I understood correctly, it sounds like the proportion of all of the
> drug abuse underway in terms of lifetime nonmedical use which is due
> to modified forms of opiates is actually very small and most of that
> is associated with polydrug use.
>
> Another way of look at it is proportion of prescriptions. So, of the
> prescribed drug, what proportion ends up being misused, and if I
> understood these numbers correctly, that may be fairly high.
>
> The question is really to Mr. Gfroerer and Dr. Rigoni to make sure I
> have got the numbers right. If I understood the numbers correctly,
> basically, there is roughly 2.5 million new users each year of
> nonmedical use of pain relievers in recent years. Roughly 10 percent
> of that would be OxyContin, so that is about 250,000 people.
>
> The total number of new prescriptions for OxyContin in the recent year
> was about 6 million. Even assuming that the average person on the drug
> got two prescription, that drops it down to 3 million. That is 250,000
> divided by 3 million or were approaching 10 percent of the
> prescriptions are associated with nonmedical use.
>
> Are those numbers correct?
>
> DR. KATZ: Who wants that one?
>
> \[Laughter.\]
>
> MR. GFROERER: I certainly can\'t speak to your data on prescriptions,
> but the numbers that you cited on the OxyContin and the nonmedical
> pain reliever use were correct, about 2 to 2 1/2 million new users
> each year. Now, we don\'t know how many of those were OxyContin new
> users. We can\'t tell which was used first, whether they first used
> OxyContin and then moved on to other drugs.
>
> We only know that of those 7 million new users within the past three
> years of the pain relievers, about 10 percent, well, I think it was 9
> percent had ever used OxyContin. In total, about 1.9 million have ever
> used OxyContin nonmedically.
>
> DR. STROM: So, that 9 percent, because it comes from lifetime use, and
> given the time trends we are seeing, might actually be an
> underestimate if we had data available from 2001 as opposed to
> lifetime use.
>
> MR. GFROERER: It is 9 percent of the new users, not 9 percent of all
> lifetime, because there is 29 million lifetime nonmedical users. It is
> only those 7 million are the recent new users, and 9 percent of those
> had used OxyContin.
>
> DR. STROM: So, then, of the 250,000 users\--
>
> MR. GFROERER: I don\'t have that number. What is the 250,000?
>
> DR. STROM: I was looking at your graph before that and it was roughly
> 2 1/2 million new users and roughly 10 percent of those, 9 percent.
>
> MR. GFROERER: Over the three-year period, those 7 million new pain
> reliever users, nonmedical users, 9 percent, which would be about
> 700,000 ever used. I don\'t know that it was 250,000 each year.
>
> DR. STROM: These are close enough as approximations, I am just
> changing it to annual numbers, so that it is roughly 250,000. What are
> the total number of ideally newly prescribed patient getting OxyContin
> each year? As far as I can tell from the NPA data, it looked like
> there were 6 million prescriptions.
>
> MR. GFROERER: I can\'t answer that one.
>
> DR. RIGONI: Because the DEA does scheduled opioids, every prescription
> would be kind of representative of a new patient to therapy, so it is
> hard to tell from the NPA data because it\'s not longitudinal how many
> people are actually new to opioid therapy, because everyone would be
> new.
>
> DR. STROM: How about from the NDTI data, though, you could tell what
> proportion of prescriptions are new versus refills?
>
> DR. RIGONI: Technically, no, because there are no refills for Schedule
> II opioids, so they wouldn\'t be counted as refills, they would be all
> counted as new prescriptions.
>
> DR. STROM: But my 6 million is a correct read of your data there?
>
> DR. RIGONI: Right, and also it is kind of hard because it is comparing
> apples and oranges, where we have medical use of opioids and NPA data,
> and they are actually finding out about nonmedical use of opioids, so
> it is kind of hard to compare.
>
> DR. STROM: But it sounds like my calculations are correct, that given
> OxyContin is a chronically used drug, if there are 6 million
> prescriptions written for it in a recent year, if you even assume the
> average person got two prescriptions, which may be an underestimate if
> a lot of these people are on chronic therapy, then, you are talking
> about 3 million users in that year, new users, sorry, users in that
> year, and you are talking about 250,000 people who used it for
> nonmedical purposes to compare that to, comparing the two data
> sources.
>
> DR. RIGONI: I guess I would have to look at more longitudinal data to
> see if that is correct, two prescription per year assumption, but I
> don\'t know that off the top of my head.
>
> MR. GFROERER: Just to follow-up, though, in terms of the 250,000
> calculated new users, those people could be users the next year. The
> new use doesn\'t mean that is the only year that those people used, so
> they could be users the next year and the year after that.
>
> DR. ARONSON: I have a question for Ms. Trunzo and I promise you it
> won\'t involve numbers.
>
> I noticed on your graphs that there is clearly a regional difference
> in the absolute number of admissions to the treatment and episodic
> data set. Was there an equal, if you will, propensity of increase over
> the years even though the absolute number was different? Did you see a
> regional difference in the change, if you will, the slope of increase
> over the years?
>
> MS. TRUNZO: I haven\'t looked at that.
>
> DR. ARONSON: The reason I ask is that you showed a graph where you
> mentioned the narcotic analgesic admissions in some states.
>
> MS. TRUNZO: Those were rates.
>
> DR. ARONSON: I noted that California was particularly flat relative to
> the other states on your graph. Can you speak to that?
>
> MS. TRUNZO: Only to say that their rate probably has remained stable
> as indicated in the graphic, however, I included that their
> preliminary data in the slides for 2001 and 2002 because they account
> for such a large number of admissions.
>
> DR. ARONSON: The corollary to that, and it\'s an observation I had
> with some of my colleagues during the break, was that California, I
> would note, has enacted some educational, if you will, linkages to
> pain management to their CME expectations, and I just wished to make
> that observation.
>
> MS. TRUNZO: As I also said in terms of discussing TEDS\' limitations,
> it does not include all admissions, and the proportion of admissions
> that it might include would vary from state to state depending on the
> individual system, so it is possible that in California, some of the
> admissions are not being reported to TEDS that might affect the rates
> had we known about them.
>
> DR. KATZ: Dr. Portenoy.
>
> DR. PORTENOY: I guess I am coming at this from where Dr. Strom is
> coming at it and just trying to understand it, because we have had the
> marked increase in the medical use of controlled prescription drugs in
> the last few years, which some of us who do pain management think
> might be a good thing given the base rate of undertreated pain.
>
> Clearly, the data together suggest that there has been an increase of
> abuse and the adverse outcomes associated with abuse, and it is a
> whole lot of numbers. I mean I did try to focus and I probably
> absorbed about 3 percent of them, and I am just trying to understand
> you who work with the numbers all the time if you could help us
> interpret what we are looking at in terms of the change over time in
> the abuse indicators that you all work with given the limitations with
> respect to this issue of change in controlled prescription drug abuse
> and adverse outcomes.
>
> It is obviously a noticeable change, the graphs all changed, the
> curves are all going up, but have we seen historically other drugs
> that look like this? Is there some sense, regionally speaking, that it
> is linked to where the largest increases of controlled prescription
> drug for medical purposes is happening? Is there any way of
> interpreting these data other than just a conclusion that, yes, at a
> time of increasing medical use, you are also seeing some increased
> abuse, which is like no surprise?
>
> MS. TRUNZO: I will speak first for TEDS. Changes in TEDS tend to occur
> very gradually, so whenever we see a sharp increase, I think that
> something real is going on there, however, as Judy mentioned in her
> presentation, other opiates represent a very small percentage of
> TEDS\' admissions, so the numbers are small. So, therefore, it is easy
> to see a large percentage increase when there is an increase in the
> numbers.
>
> However, you know, the trend has been consistent since 1997. It\'s not
> going like this that might make you think some sort of error was
> creeping in.
>
> DR. PORTENOY: Just to follow up on that, is there any way from the
> data to sort out the difference in the adverse outcomes that would
> originate from diversion, diversion to the illicit market versus what
> is actually being prescribed by doctors speaking to Brian\'s point?
>
> MS. TRUNZO: No, we can\'t do that.
>
> DR. KATZ: Dr. Maxwell.
>
> DR. MAXWELL: This is a little bit off topic, but there was one thing
> in Mr. Gfroerer\'s presentation that caught my eyes, because often we
> don\'t associate hallucinogen use with the use of other opiates, but
> the National Household Survey is showing 89 percent of the OxyContin
> users also used other hallucinogens.
>
> Did you break out which hallucinogens are most associated with it?
> This is kind of an interesting change in who is using it. It\'s club
> drug users?
>
> MR. GFROERER: Well, I don\'t have that data. It is possible to look at
> that, though, we could look at the specific hallucinogens and see
> which ones are associated with OxyContin, but I don\'t have it now.
>
> DR. KATZ: Dr. Gillett.
>
> DR. GILLETT: Thank you. It strikes me that veterans are rather ignored
> here. They are either institutionalized and excluded or somehow not
> counted, and I was curious as to how you tapped into that population,
> which has a history of drug abuse and other issues critical to their
> health.
>
> MS. TRUNZO: In TEDS, admissions to Department of Veterans Affairs
> facilities are excluded, however, the data might include veterans who
> were receiving treatment at state-funded facilities. They weren\'t
> broken out in my presentation although we could do that. There are
> quite a few veterans in the TEDS database, but the federally-owned
> facilities simply aren\'t part of it.
>
> DR. GILLETT: Along that same line, how does that work with rural
> communities which are not served by emergency rooms, do we
> undersample, underreport, ignore, what?
>
> MS. TRUNZO: I will turn this over to Judy in a minute. TEDS, as a
> rule, does not include emergency rooms, it includes specialty
> treatment facilities or substance abuse treatment units within a
> hospital.
>
> DR. BALL: The DAWN sample of hospitals is designed, so that we can
> produce estimates for the nation as a whole, and we have oversamples
> in 21 major metropolitan areas that we can produce estimates for each
> of those areas.
>
> The challenge of collecting data on drug abuse in rural areas, and
> certainly Joe can probably talk about even more than I, but basically,
> it is not feasible for us, given the constraints of budget, to produce
> rural estimates from emergency department sample in DAWN.
>
> Rural areas are included in the national estimate, but all the
> metropolitan areas are, as well. One of the ways that we are beginning
> to try to get a handle on this is on the medical examiner side of
> DAWN, that the medical examiner data, too, has been sort of skewed
> toward metropolitan areas in the past.
>
> We have begun an initiative to bring on some statewide medical
> examiner systems, and many of these come from states that have
> substantial rural populations, so we are sort of looking at the state
> initiative as a way of trying to get some comparable data on drug
> abuse in rural areas, and that is beginning this year.
>
> DR. KATZ: Thanks, everybody, especially our colleagues from SAMHSA for
> pitching in right before lunch.
>
> Two announcements before we adjourn for lunch. First of all, we will
> regroup here at 1:45 to start the afternoon session. Secondly, any
> speakers for the open public forum, please, as we begin our afternoon
> session at 1:45, situate yourselves here in this seating area to my
> left, so that we can bring people up and down relatively efficiently
> when we get started.
>
> Thanks, and I will see you at 1:45.
>
> \[Whereupon, at 1:00 p.m., the proceedings were recessed, to be
> resumed at 1:45 p.m.\]
>
> [A F T E R N O O N P R O C E E D I N G S]{.underline}
>
> \[1:50 p.m.\]
>
> DR. KATZ: While the slides are being queued up, let me introduce Dr.
> Elizabeth Willis, who is the Chief of the Drug Operations Section of
> the Drug Enforcement Administration, and she will be addressing us on
> Diversion of Prescription Opiates.
>
> **Diversion of Prescription Opiates**
>
> DR. WILLIS: Good afternoon. I would like to thank this committee for
> the opportunity to address you regarding DEA\'s concern on the control
> of opioid pharmaceuticals and our specific concern with the diversion
> of high-dose, single-entity prescription opiates.
>
> The Controlled Substances Act of 1970 assigned the DEA the legal
> authority to regulate controlled substances. Through this legislation,
> DEA is mandated to prevent, detect, and investigate the diversion of
> legally manufactured controlled substances, while at the same time,
> ensure that adequate supplies are available to meet legitimate
> domestic medical and scientific needs.
>
> The CSA established a closed system of distribution of controlled
> substances that requires the registration of all handlers of these
> drugs including manufacturers, distributors, importers, exporters,
> pharmacies, and practitioners.
>
> Production quotas, as well as recordkeeping and security requirements,
> are designed to enable DEA to track and safeguard potentially
> dangerous controlled substances as they are transferred from the
> manufacturer to the ultimate user.
>
> However, despite these controls and our best efforts, the diversion
> and abuse of pharmaceutical controlled products continues to pose a
> significant problem. New, higher dose, single-entity products,
> particularly opiates, are of particular concern given our experience
> with OxyContin.
>
> For the sake of clarity, DEA defines diversion as the movement of a
> controlled substance from the legitimate distribution chain into the
> illicit market.
>
> Why are prescription drugs so popular with the drug abusing
> population? There are several reasons for this. Number 1 is quality
> and quantity. Abusers know that prescription drugs are manufactured
> under strict government control. They know the drugs do not contain
> adulterants or contaminants, and they know the exact dosage they are
> taking. These assurances are not available on street drugs.
>
> In addition, the amounts of the drug found in the new high-dose
> opioids makes these drugs particularly attractive to narcotic addicts.
>
> Second, there is the belief that if my doctor prescribed it for me, it
> can\'t be bad, and most often this is true as there is no question
> that pharmaceutical drugs are beneficial when used appropriately.
> However, care must be taken that the right patient gets the right drug
> at the right time and in the right dose in order to ensure its
> efficacy.
>
> Also, there is the belief that if the user does not inject the drug,
> he is not truly a drug abuser. In U.S. society, the stigma of being an
> I.V. drug abuser often does not carry over to those who swallow a
> pill.
>
> There is also the cost. When controlled substances are obtained via a
> prescription, oftentimes the cost is covered by health insurance or by
> Medicaid, which makes the cost to the user minimal. However, on the
> street, pharmaceutical controlled substances command a very high price
> and this encourages the diversion of these drugs.
>
> Sometimes the abuser will turn to prescription drugs when street drugs
> are not available, or they will use prescription drugs in combination
> in order to potentiate the effect of street drugs.
>
> Finally, prescription drugs are readily available and distributed
> through open commercial markets unlike street drugs, which are
> distributed through a series of illegal and underground trafficking
> networks.
>
> Today, the vast majority of diversion of controlled substances is at
> the retail level, which includes diversion by practitioners and
> pharmacists and consumers. The means used to divert prescription
> opiates are those typically used by diverters of all pharmaceutical
> controlled substances and include illegal and indiscriminate
> prescribing by practitioners. This includes the four D\'s previously
> referred to as the doctors who are duped, dishonest, disabled, and
> dated.
>
> There is also illegal dispensing by pharmacists. Pharmacy theft is
> another common method of diversion including armed robbery, night
> break-ins, employee theft, and customer pilferage. There are forged
> and fraudulent prescriptions.
>
> There are patients who go to doctors claiming false medical needs.
> There are doctor shoppers who travel from doctor to doctor looking for
> an easy mark who will readily write prescriptions or who can be duped
> by false medical records and illnesses.
>
> There is foreign diversion and the subsequent smuggling into the
> United States. There is also in-transit theft of controlled substances
> during the transportation process from the manufacturer to the retail
> pharmacy. In fact, during this past year, we have experienced several
> armed hijackings of entire tractortrailers of controlled substances.
> This has been a rather unusual event and one that we are particularly
> concerned about.
>
> There is also distribution through the internet. Many internet web
> sites advertise and sell controlled substances with little or no
> oversight to encourage or ensure that the drugs are being used for a
> legitimate medical purpose.
>
> In order to keep abreast of diversion trends, the DEA Office of
> Diversion Control gathers information and intelligence from several
> sources. The DEA\'s automated reports and consolidated order system,
> known as ARCOS, was developed to monitor and maintain current and
> historical records of selected controlled substance inventories and
> transactions from the point of manufacturer to the point of retail
> sales where it is dispensed to the ultimate consumer.
>
> The DEA gathers drug exhibit data from state and local forensic
> laboratories through the National Forensic Laboratory Information
> System. Intelligence is also gathered from other federal agencies,
> state and local counterparts, and regulatory agencies.
>
> In addition, the DEA is alerted to possible illegal activities and
> abuse by family members, local law enforcement, and state authorities.
> Through these sources, DEA finds that while there are some unique drug
> trends in each geographic area, overall, the abuse and diversion of
> controlled substances is consistent throughout the country.
>
> I would now like to take this opportunity to identify for you some of
> the prescription opiates that DEA finds to be commonly abused and
> diverted. In many of these cases, these drugs are abused in
> combination with each other and with other types of controlled
> substances, such as benzodiazepines. This polydrug abuse makes
> successful treatment even more difficult and contributes to overdoses
> and death.
>
> Historically, DEA has found that the immediate-release opiate products
> of hydrocodone, hydromorphone, and oxycodone are among the most
> diverted prescription drugs. Once diverted from legitimate channels,
> these drugs can be used as a substitute for illicit narcotics and are
> frequently trafficked on the street by individuals and structured
> organizations.
>
> The costs of purchasing these prescription drugs on the illicit market
> vary from drug to drug and from geographic area to geographic area.
> Most often, recognizable brand names are preferred over generics and
> command a higher price on the street.
>
> Hydromorphone has been one of the most diverted and abused
> prescription opiates for the past 30 years. Hydromorphone 4 and 8
> milligram tablets are the most subject to diversion and abuse. As far
> back as the 1970s, Dilaudid has been known on the street as \"drug
> store heroin.\" Current street prices for a single 4-milligram
> Dilaudid tablet, the most preferred strength, range from \$5.00 in the
> Milwaukee area to as high as \$80 in Richmond, Atlanta, and San Diego.
> The nationwide average price for a single 4-milligram Dilaudid tablet
> is \$40 per tab.
>
> Oxycodone immediate-release combination and single entity products are
> also very popular among the narcotic-abusing population. The most
> common and popular combination oxycodone products are Percodan,
> Percocet, and Tylox. Diversion of these products occurs in every area
> of the country and the street price runs between \$10 and \$30 per
> tablet.
>
> For the last three years, DEA\'s National Forensic Laboratory
> Information System reported oxycodone and hydrocodone account for
> approximately 70 percent of all narcotic analgesic drug exhibits
> analyzed by state and local forensic labs.
>
> The DEA Quarterly Reports indicate that hydrocodone products are the
> most sought after licit drugs and are diverted in every geographic
> area of the country with street prices averaging around \$5.00 per
> tablet.
>
> As a group, hydrocodone products are the most prescribed and the most
> diverted of the opioids. Because they are Schedule III controlled
> substances, hydrocodone can be telephoned in to pharmacies and can be
> refilled, so they have a higher association with doctor shopping and
> fraudulent prescriptions.
>
> The most popular brand names of hydrocodone products diverted include
> Lortab, Vicodin, Lorcet, and Tussionex. Because there is a steady
> increase in abuse and diversion of these products, DEA is currently
> reviewing hydrocodone drug products for possible control status change
> from Schedule III to Schedule II.
>
> The new generation of high-dose, single-entity controlled-release
> products, or sustained-release products, such as MS-Contin, Duragesic,
> and OxyContin pose special problems for law enforcement.
>
> The problems associated with OxyContin have been particularly
> devastating. OxyContin is a valuable and efficacious drug when used
> properly, however, the abuse and subsequent diversion of OxyContin has
> increased dramatically since its introduction into the market.
>
> Once word of this product made its way to the street, its popularity
> skyrocketed. DEA has never witnessed such a rapid increase in the
> abuse and diversion of a pharmaceutical drug product, and we believe
> there are a number of reasons for this.
>
> OxyContin is marketed in 10, 20, 40, and 80 mg tablets. While the
> higher dose of active ingredient facilitates continuous and effective
> pain relief, it also makes the product more attractive to drug
> abusers. In simple terms, the drug abuser gets more bank for his buck
> by buying one OxyContin 80 mg tablet than in one Percodan tablet
> containing 5 mg of oxycodone.
>
> Put another way, the abuser would need to take 16 Percodan tablets to
> get the same effect or the same quantity of narcotic as found in one
> 80 mg OxyContin tablet. In addition, when the sustained-release
> formulation is compromised, the entire dose of active ingredient is
> released at one time, thus creating a potent narcotic high. This
> immediate release of the active ingredient can have deadly
> consequences for opiate-naive users whose bodies have not developed a
> tolerance to the narcotic.
>
> The DEA also believes that the original marketing of OxyContin
> contributed to its abuse and diversion. OxyContin was promoted to a
> wide range of medical specialties for a variety of indications. Many
> of the physicians were family practitioners and internists, not all of
> whom were trained in pain management regarding the proper use of such
> a high dose narcotic.
>
> Because OxyContin contains the active ingredient oxycodone, it was
> frequently equated with other products such as Percodan. But as stated
> before, OxyContin contains 2 to 16 times the dosage of oxycodone as
> Percodan. The effects of taking such a potent narcotic were not fully
> recognized by either physicians or consumers.
>
> Problems with OxyContin occurred relatively soon after its initial
> marketing.
>
> \[Slide.\]
>
> By the year 2000, DEA noted a dramatic increase in the illicit
> availability and abuse of OxyContin. By mid-2001, OxyContin reached
> record levels of diversion and abuse. Initially, diversion was noted
> in rural areas of the eastern United States, particularly in parts of
> Appalachia and New England.
>
> It very quickly gained popularity among prescription drug abusers, and
> it was not long before OxyContin abuse and diversion spread to other
> parts of the country including South Carolina and Florida.
>
> While at first the abuse and diversion of OxyContin seemed to remain
> east of the Mississippi River, within the past couple of years, DEA
> has seen an increased diversion spread into western parts of the
> country including Alaska and Hawaii.
>
> Street names for OxyContin include C, OC, Ox, and Execution. Drug
> abusers quickly found the means to compromise the time release
> mechanism of OxyContin by removing the coating or by crushing the
> tablet which allows for the complete dose of oxycodone to be
> administered at one time by swallowing, injecting, or snorting.
>
> Its abuse has led to an OxyContin subculture with the manufacturer\'s
> promotional items often found for sale on E-Bay.
>
> \[Slide.\]
>
> In one DEA investigation, a defendant was found to have this tattoo on
> his arm. When asked what the tattoo stood for, the defendant stated
> that by taking an 80 mg and a 40 mg tablet together just one time, the
> user would be hooked for life and his life would be hell.
>
> DEA field offices report that the 40 mg OxyContin tablet is the most
> popular dose sold on the street and that all dosages sell for an
> approximately \$1.00 per milligram.
>
> Methods of diversion of OxyContin run the full spectrum of those
> previously identified. Illegal and indiscriminate prescribing by
> unscrupulous medical professionals, doctor shopping, and forged
> prescriptions are common methods of diversion.
>
> DEA investigations have also uncovered organized rings of individuals
> obtaining OxyContin by fraudulent means of doctor shopping or
> prescription forgery. Oftentimes these individuals use some of the
> drug themselves and then sell the remainder on the street to cover
> their own drug habits.
>
> Other investigations have found drug organizations that traffic in
> illicit street drugs, such as cocaine and Ecstasy, are now also
> trafficking in OxyContin.
>
> In South Carolina, a group of seven physicians was investigated and
> indicted for the illegal distribution of OxyContin. The investigation
> found that patients would wait up to four hours to see one of the
> physicians who would write prescriptions for OxyContin for nonmedical
> reasons. Patients traveled from all parts of South Carolina and from
> out of state in order to get their OxyContin prescriptions.
>
> The prescriptions were then filled in nearby pharmacies and taken back
> to local communities where they were sold on the street. The DEA
> determined that the physicians diverted in excess of 1,080,000 tablets
> of OxyContin.
>
> As a result of this investigation, the physicians are currently
> awaiting sentencing for the illegal distribution of OxyContin.
> Regrettably, one doctor was so despondent over his involvement that he
> committed suicide.
>
> When interviewed by the DEA, the primary target and owner of the
> clinic said that his only goal in the operation of the clinic was to
> make as much money as possible without getting caught. He admitted
> that all he and his colleagues did was distribute narcotics.
>
> His hiring process started with seeking out desperate and willing
> doctors for job placement and he instructed the placement agencies to
> only refer those doctors who would write large amounts of narcotics.
>
> His pain protocol was that everyone coming to the clinic would receive
> a narcotic and if the patient did not want narcotic, they could go
> elsewhere. The clinic also had a \"don\'t ask, don\'t tell\" policy
> about histories of drug abuse and patients were deliberately not asked
> if they had drug problems.
>
> \[Slide.\]
>
> The chart on the screen shows the distribution of OxyContin in the
> State of South Carolina for the years 2000 to 2002. While DEA cannot
> avow that the drop in OxyContin distribution wa due solely to the
> closing of this clinic, it is interesting to note the sharp decline
> beginning in June 2001, the same time that the clinic was shut down.
>
> In many parts of the United States, thefts of OxyContin through armed
> robberies and night break-ins of pharmacies have increased over the
> past three years. The violence typically surrounding armed robberies
> is of particular concern to DEA and other law enforcement agencies.
>
> In the year 2000, DEA received reports of 43 armed robberies of
> pharmacies nationwide where OxyContin was taken. In the year 2002,
> there were 277 such armed robberies. Particularly hard hit has been
> the State of Massachusetts, where almost 250 armed robberies were
> reported in an 18-month period.
>
> Due to the large number of robberies throughout the state, many of the
> pharmacies in Massachusetts discontinued selling OxyContin. Others
> hired armed security guards to patrol their premises during business
> hours.
>
> The pharmacies were not the only targets for armed robberies. In one
> particularly heinous incident, two armed men entered a nursing home in
> Massachusetts at 1:30 in the morning. They held 6 nurses and 40
> patients at gunpoint and demanded all OxyContin be turned over to
> them. Fortunately, once they received the drugs, the armed gunmen left
> and no one was physically harmed.
>
> I would like to share with you the experience DEA found in
> Southwestern Virginia regarding the abuse and diversion of OxyContin.
> Due to the devastation that OxyContin abuse was having in this area,
> DEA conducted a threat assessment of the problem in 2001.
>
> This study found that OxyContin abuse in Southwestern Virginia
> exhibited a sharp rise beginning in the spring of 1999. Considerable
> law enforcement resources were devoted to curb the OxyContin diversion
> including the creation of formal and informal drug task forces
> combining federal, state, and local resources.
>
> Through these combined efforts, several OxyContin trafficking
> organizations were identified and disrupted. However, the area then
> experienced an increase in the number of pharmacy armed robberies. In
> addition, homes were broken into for the sole purpose of stealing
> OxyContin from legitimate pain patients.
>
> As a result of this crime, many local jails were filled to double
> their capacity and reported that more than half of their inmates were
> incarcerated due to OxyContin related crime.
>
> The study also found that drug treatment centers in Southwestern
> Virginia were experiencing an increase in the number of intakes due to
> OxyContin abuse. One treatment facility stated that in 1999, they had
> treated 18 patients for prescription narcotic addiction. However,
> between March 2000 and January 2001, the facility had treated more
> than 1,000 patients, with over 98 percent of the patients stating
> OxyContin was their drug of choice.
>
> Less than 2 percent of the patients reported a preference for heroin.
> One OxyContin addict interviewed related some of the desperate lengths
> abusers will go to in order to get their fix, including using water
> from mud puddles in order to inject the drug, or using needles
> previously used to vaccinate dogs.
>
> \[Slide.\]
>
> In response to growing concern among federal, state, and local
> officials about the dramatic increase in the illicit availability and
> abuse of OxyContin, DEA initiated its OxyContin Action Plan in May
> 2001 as a comprehensive effort to prevent its diversion and abuse.
>
> This was the first time that DEA had found it necessary to take such a
> comprehensive approach to a particular brand name controlled substance
> drug product. These efforts are not intended to impact on the
> availability of OxyContin for legitimate medical use.
>
> The OxyContin Action Plan is ongoing and has four primary elements.
> Individually, the elements will not result in success. To succeed, we
> must have cooperation, coordination, support and participation from
> all four of the following elements:
>
> First, the four elements are enforcement and intelligence, which
> includes coordinated investigations targeting individuals and
> organizations trafficking OxyContin.
>
> Regulatory and administrative, where DEA and other regulatory agencies
> utilize all of our means to prevent and pursue action necessary to
> make it more difficult for abusers to obtain OxyContin.
>
> We also seek industry cooperation. DEA has sought increased
> cooperative efforts with all aspects of the pharmaceutical industry,
> and we view voluntary compliance from industry as the key to this
> element.
>
> We also participate in Awareness/Education and Outreach Initiatives.
> This includes participation at several levels including town-hall
> meetings, demand reduction presentations to parent groups, and
> cooperative efforts with ONDCP. In addition, DEA includes information
> on OxyContin abuse on the Office of Diversion Control public web site
> at www.deadiversion.usdoj.gov.
>
> Since the OxyContin Action Plan was initiated in mid-2001, DEA has
> conducted over 400 investigations of the diversion and trafficking of
> OxyContin. Well over 110,000 work hours have been spent on these
> investigations with the result of almost 600 individuals arrested.
>
> Approximately, 60 percent of the cases initiated were in the retail
> profession including doctors and pharmacists. Doctor shoppers,
> forgeries, and individuals arrested in armed robberies and burglaries
> accounted for 40 percent of the investigations.
>
> There has been concern expressed by some pain physicians that they
> could be investigated by DEA or have legal sanctions placed on them by
> DEA or state medical boards simply because they prescribe OxyContin or
> other strong opioids.
>
> I would like to assure you that the intent of DEA is to target the
> illicit diversion and abuse of controlled substances. We recognize the
> place that pharmaceutical controlled products have in the treatment of
> a variety of medical needs, including pain management, and we work
> closely with state medical boards and associations to ensure our
> investigators are up to date on the latest guidelines.
>
> In conclusion, I would like to say that DEA is committed to protecting
> the American public\'s health and safety from the serious and negative
> consequences associated with the diversion of pharmaceutical
> controlled substances.
>
> In this effort, we will not be deterred. DEA has seen firsthand the
> devastation that all drug abuse, including prescription drug abuse,
> can wreak on our fellow Americans. Lives can be lost and families can
> be destroyed.
>
> During the past few years, DEA and the entire healthcare community
> have learned new lessons on the damage a prescription drug can do when
> not appropriately prescribed or used.
>
> From our experience with the diversion of OxyContin, we have found
> that a targeted effort to eliminate diversion of particular products,
> such as our action plan, may be necessary and that it can be an
> effective weapon in the fight against drug diversion.
>
> However, as always, prevention of drug abuse is the most effective
> tool against diversion. The devastation wrought by the abuse of
> OxyContin has been a hard lesson for all of us. We must learn from
> this experience that once a drug has gained popularity among the
> drug-abusing population, there are few actions that can dramatically
> alter the demand for the drug on the street.
>
> Law enforcement efforts are, in reality, simply clean up of a problem
> that has gone out of control. Steps must be taken to ensure that
> comprehensive risk management plans are in place before any new
> high-potency narcotic is approved for release to the American people.
>
> Thank you. I think I have time to entertain a couple of questions.
>
> DR. KATZ: It is still yellow. We have time for a question or two. Dr.
> Dworkin.
>
> DR. DWORKIN: Does the DEA have any data regarding what percent of
> diverted drug remains local and what percent, if you will, crosses
> state lines and ends up being used elsewhere?
>
> DR. WILLIS: I don\'t have data to that effect and it just depends on a
> case-by-case basis. We do know of many examples where we have very
> organized criminal rings that will traffic from Florida up to New
> York, for example. We had an example of that recently.
>
> Some of the local doctor shopping and prescription forgery remains
> local area. I am afraid I don\'t have those specific statistics for
> you
>
> DR. KATZ: Dr. Crawford.
>
> DR. CRAWFORD: Thank you. In a similar vein, can you quantify for us
> and estimate how much of the problem may be due to the rogue internet
> sites out where it is out of the United States, not based in the
> United States?
>
> DR. WILLIS: Well, foreign internet sites are a particular problem, and
> DEA is very aware of this issue. We are working in several different
> arenas with our foreign counterparts. It is difficult to investigate
> and curtail the smuggling or diversion of these drugs from foreign
> sources, simply because we do not have immediate control over these
> sources.
>
> We are putting a lot of effort into identifying them. As far as
> quantitating how much is coming in, no, I am afraid I can\'t do that.
> There are new sites that come up on the web every single day. We do
> know that probably the drugs that are most purchased or available over
> the internet as far as controlled substances would be weight control
> drugs and hydrocodone, but there are a number of web sites that
> advertise the higher schedule narcotics also.
>
> DR. CRAWFORD: And a very quick question. We have been told this
> morning by Mr. Woodworth that DEA establishes quote limits on the
> manufacture of the products. For any of these predominant products we
> are discussing today, have any of the manufacturers met or approached
> their limit, are they well below those limits?
>
> DR. WILLIS: Well, the quotas are based also upon estimates submitted
> by the drug manufacturers as to how much they will be producing each
> year, so the vast majority of them produce what they submit.
>
> DR. KATZ: Dr. Shafer.
>
> DR. SHAFER: I heard two different kinds of diversion problems and to
> my mind they are quite different. One is clearly criminal diversion,
> hijackings, home invasions, thefts, or physicians who are basically
> running criminal enterprises to make drugs available.
>
> The other is diversion I would say at the level of the individual
> patient, who may be doctor shopping because they are addicts, but they
> are essentially seeking drug for their own use. I somewhat despair as
> a physician of being able to give you any guidance on, you know,
> hijacking trucks. It is just not an area that I have a lot of
> expertise or experience with.
>
> How much of the diversion is frankly criminal activity and how much of
> it is something that happens as an adverse outcome of routine clinical
> care?
>
> DR. WILLIS: Well, it is difficult really for me to quantify that. DEA,
> we expend most of our resources at the criminal level, so I can
> address as far as the number of investigations we have had and the
> number of defendants we have arrested, the number of armed robberies,
> and that type of thing. We do not have the resources to fully
> investigate diversion through doctor shopping and prescription
> forgery. We work primarily in concert with our local law enforcement
> agencies, and they are the ones that primarily do the doctor shopping
> and prescription forgery.
>
> So, I don\'t have available statistics as to how much is associated
> with criminal versus individual patients. What I can tell you is that
> physicians and obviously it\'s a small number of physicians who are
> involved in criminal activity, we recognize that the vast majority of
> doctors are very law-abiding and only want to help the public, but a
> single physician has an unlimited ability to write prescriptions, and
> until law enforcement or the regulatory boards catch up with their
> activities, so one physician can do a lot more damage than a dozen
> prescription forgers.
>
> DR. KATZ: Thank you. I just can\'t help but emphasize the importance
> of that question about how critical it is to design any rational
> program to combat prescription opioid abuse without knowing what
> proportion of the cases of prescription opioid abuse arrive to it from
> different pathways, it is impossible to rationally construct methods
> to reduce the ultimate problem not knowing which pathway to reduce.
>
> DR. WILLIS: That has been a problem we have been dealing with for
> years.
>
> DR. KATZ: So, I would just submit to the committee, since one of the
> aspects of our agenda in this meeting is to decide what data we need
> in order not only to construct a risk management program, but to
> monitor the results of the program, I would ask the committee to keep
> this question in mind as we get to that discussion later today or
> tomorrow.
>
> I have got a couple of people ahead of you, Dr. Gillett, but I will
> put you right on the list.
>
> Dr. Cush.
>
> DR. CUSH: I haven\'t seen any information on the use of taggers or
> tracers, or anything like that in these batches. Do they do that or is
> that confidential?
>
> DR. WILLIS: That type of thing would be proprietary information.
>
> DR. KATZ: Dr. Portenoy.
>
> DR. PORTENOY: I am just look at this problem as you presented it, as
> one that would have to include law enforcement, the availability of
> treatment, demand reduction, and then some controls on the prescriber
> side.
>
> I am just wondering whether DEA collects data about whether or not the
> regional differences, the regional distribution in abuse may correlate
> with the availability of treatment, the differences in the
> availability of treatment in different states, or the expertise of
> local law enforcement in different states, or educational programs
> directed toward the public for demand reduction in different states,
> whether you collate any information that could help us try to
> understand the regional differences.
>
> DR. WILLIS: I am not aware that we have any information at the moment,
> but I think that would be a very interesting study for us to
> undertake. Particularly, we do have all of the distribution data
> through our ARCOS information system. We have treatment information as
> to where the narcotic treatment programs are located and some type of
> correlational study would be interesting to do.
>
> DR. BRIL: Along these lines with differences in regions, I was
> wondering if the DEA has any information on the use of, say, OxyContin
> in\--is it the Netherlands where opiate use is decriminalized, the
> European country where it is not a crime, I guess, to use these drugs?
>
> DR. WILLIS: I don\'t have information on that available, but we could
> try to find some out and get back to you.
>
> DR. BRIL: That would be kind of answering the question directly about
> what comes from prescription use and what comes from recreational use
> if you had numbers from a country where it wasn\'t criminalized to
> take these drugs.
>
> DR. KATZ: Dr. Ciraulo.
>
> DR. CIRAULO: I have just a couple of comments really related to the
> experience that we have had in South Boston, which is a small
> community. One of the things I would like to point out is it is not as
> simple as an OxyContin problem.
>
> The problem started several years ago with actually a heroin problem,
> that the heroin entered the neighborhood in such a cheap and pure form
> that adolescents were able to get it. What we saw is a decline in
> cocaine use, then using heroin, then, a switch to OxyContin. So, I
> think it is a complicated problem, it is not just an OxyContin
> problem.
>
> The second problem is a real concern about the level of resources that
> are being put into stopping the diversion. I can go into South Boston
> and identify, and I know the police can go do the same thing, who is
> pushing, and what happens when they identify these folks, they keep on
> moving farther south and farther south, but we have seen 30 overdoses
> of adolescents in the past month on a mixture of heroin and OxyContin.
> So, I am concerned.
>
> Are there resources at the state level? You saw Massachusetts was one
> of the ones way up there. Are there enough resources and what can we
> do to\--
>
> DR. WILLIS: Well, I don\'t think there are enough resources nationwide
> to combat the problem. Certainly, there aren\'t at the federal level,
> and the state and local police departments are stretched to the limits
> also. So, no, I don\'t think there are enough resources.
>
> I don\'t think it\'s a matter of not wanting to work on this problem.
> It\'s simply a matter of not having the budget and the resources
> available to address the problem the way it should be.
>
> I also agree with you in your first part of the comment about it
> isn\'t just an OxyContin problem. It is a very complex problem. One
> type of drug abuse leads to another type of drug abuse and
> experimentation. When the heroin is not available on the street, they
> will turn to the pharmaceutical narcotics and vice versa, so it is a
> very complex problem.
>
> DR. KATZ: Thank you very much, Dr. Willis, for sharing your thoughts
> with us.
>
> **Open Public Hearing**
>
> DR. KATZ: We are moving on to the open public hearing section of our
> afternoon now. First of all, let me just say that anybody who is
> planning on speaking during the open public forum now, please come up
> from wherever you are and have a seat in that section to my left.
>
> I promised that I would read this announcement about financial
> disclosures before every open public forum session, so I am going to
> keep my promise right now. This is for the speakers to pay attention
> to.
>
> Both the FDA and the public believe in a transparent process for
> information gathering and decisionmaking. To ensure such transparency
> at the open public hearing session of the Advisory Committee meeting,
> FDA believes that it is important to understand the context of an
> individual\'s presentation.
>
> For this reason, FDA encourages you, the open public hearing speaker,
> at the beginning of your written or oral statement, to advise the
> committee of any financial relationship that you may have with any
> company or any group that is likely to be impacted by the topic of
> this meeting. For example, the financial information may include a
> company\'s or a group\'s payment of your travel, lodging, or other
> expenses in connection with your attendance at the meeting.
>
> Likewise, FDA encourages you, at the beginning of your statement, to
> advise the committee if you do not have any such financial
> relationships. If you choose not to address this issue of financial
> relationships at the beginning of your statement, it will not preclude
> you from speaking.
>
> So, here is what that all boils down to. When you get up, just say who
> you are, where you are from, and financial disclosures that you have.
> You have got five minutes. The yellow light goes on at four, and the
> red light goes on at five, and then I will interrupt you and it will
> be time for the next person. So, hopefully, that makes it more clear.
>
> The first speaker will be Barry Cole. After that will be Jeffery Ebel,
> if you would like to put yourself on deck.
>
> DR. COLE: Thank you very much. Barry Cole with the American Academy of
> Pain Management. In the last year, myself or the American Academy of
> Pain Management have received funding from Abbott and G.W. Pharma,
> Jansen, Ortho-McNeil, and Purdue Pharma.
>
> \[Slide.\]
>
> This is about education I would say more than anything else. That is
> what is really important. We understand that today, that there are
> still tens of millions of people suffering that can\'t get lost in any
> debate that we talk about.
>
> \[Slide.\]
>
> Why we are really here is how to stop substance abusers from dying. We
> are at an interesting position, we don\'t really have a product defect
> per se, we have a defect in the end use of the product, and perhaps
> practitioner education can address that problem.
>
> However, there will always be public policy implications for every
> choice we make. What I worry about is that pain patients will have
> decreased access to practitioners. Already many people tell me it\'s
> just too much trouble to deal with these kinds of patients, there will
> be more barriers thrown in their way, there will be mandatory police
> checks, there will be increased costs that somebody is going to get
> stuck with.
>
> There will be more administrative burden, and I can\'t even guarantee
> that the patients will fare any better, while I can\'t absolutely
> guarantee either that abusers won\'t stop dying. The problem here is
> that they will still abuse product just like criminals still can
> obtain guns even with gun control legislation.
>
> We have always used education as the remedy in medicine. The half-life
> of medical information is about five years. Every physician expects to
> go back and retrain. We have used the model in California where the
> Academy is located now of having a mandatory 12-hour educational
> requirement to allow for relicensure of California physicians. There
> is something that the Federal Government could do - look at DEA\'s
> certificate renewal on a three-year basis as something that could be
> contingent on continuing education.
>
> The kind of education that needs to be addressed is what kind of
> patients are we putting on medication and when do we make these
> choices. It is about medical history taking. It\'s about risk
> assessment. It\'s about doing a physical examination, something that
> often isn\'t done that well.
>
> It is about developing a plan of care with measurable, behaviorally
> measurable goals, getting informed consent, maintaining an ongoing
> monitoring relationship with the patient, establishing some way of
> seeing that therapy works, and obviously, staying in compliance with
> rules and regulation.
>
> I can\'t tell you how many charts I have reviewed where it appears
> that my colleagues don\'t believe that the DEA\'s rules specifically
> apply to them. They have found loopholes, but they thought they could
> exploit.
>
> Roles for simulation-based opioid education, this is something that I
> don\'t think very many of us have thought about. Most of us went to
> medical school, nursing school, pharmacy school. We sat like sponges
> in a room and they presented a lot of information.
>
> I have recently been working with a group called Digital Think out of
> San Francisco to see if there is a way to creatively solve this
> problem through on-line education, creating an environment that would
> actually immerse practitioners in real decisionmaking processes and
> allow them to fail safely, be able to identify what they don\'t know
> and provide education to them on a real-time basis and hopefully,
> teach them something along the way.
>
> \[Slide.\]
>
> The U.S. Military loves this idea. If you think about it, because the
> consequences of bad decisions are literally lethal and also they have
> to make decisions often with imprecise information in a very short
> period of time.
>
> \[Slide.\]
>
> The difference between our traditional educational models and where we
> might want to go is being able to get past the consequences of bad
> decisionmaking from a paper and pencil test to showing what really
> could happen. I guess you could have a model where there is an
> electronic DEA agent who actually kicks down your door and you can see
> your hands being handcuffed to do the perp walk. That is possible.
>
> Knowledge being tested doesn\'t always seem relevant when you do a
> paper and pencil test. It would seem a lot more relevant when you are
> actually doing a computer simulation and certainly you would be able
> to see its applicability in real time, and obviously, passing tests
> doesn\'t prove you really know anything, it proves you passed a test.
>
> Working in a simulation model, we hope would actually lead to
> behavioral changes on the job.
>
> \[Slide.\]
>
> The Academy, like many other pain-related organizations, really is
> hoping that we can all work together. This is more than just about my
> organization or anyone else\'s. It involves law enforcement, it
> involves professional societies, the addiction community, the patients
> themselves, and even regulatory authorities.
>
> I am a former state administrator for Nevada, a place that has been
> described as the most behaviorally adverse state in the Union. I was
> the Director of Mental Health, very strange job.
>
> I think we really can work together and make a lot of good things
> happen. Don\'t be too draconian too quickly.
>
> Thank you.
>
> DR. KATZ: Thank you, Dr. Cole.
>
> Jeffery Ebel, you are next, and on deck is Dr. Van Zee.
>
> So, once again, who you are, where are you are from, any financial
> disclosures, yellow at four, red at five.
>
> DR. EBEL: Good afternoon. My name is Jeffery Ebel and I am President
> of Clint Pharmaceuticals. Clint Pharmaceuticals is located in
> Nashville, Tennessee. We are a distributor of injectable medications
> to physicians, hospitals, clinics, pain control centers, and to
> surgery centers.
>
> We distribute these products that we have, are distributed, all have
> FDA approval. We get the products in from the manufacturer, and we do
> not alter them or do anything with them in any way. We simply get them
> in and then re-ship them out.
>
> The product I am going to talk to you about is called Celestone
> Soluspan. It is a product that we do benefit from financially when the
> product is sold.
>
> I will just lay this up here for Exhibit A. However, the competitive
> products to Celestone Soluspan, Kenalog and Depo Medrol, we market
> those equally as well, and if a physician does not have access to the
> Celestone, they can order the Kenalog or Depo Medrol, and we would
> benefit from that. So, we really don\'t have in a way a horse in this
> race.
>
> Clint Pharmaceuticals works with many specialties, such orthopedics,
> rheumatologists, dermatologists, et cetera. One of these specialists
> we work with is anesthesiologists or pain care physician.
>
> We plan to work with the ASIPP in getting Celestone Soluspan available
> to their patients. I have a letter here that I am submitting as an
> exhibit from the ASIPP, which is the American Society for
> Interventional Pain Physicians.
>
> Celestone Soluspan has not been available to the physicians and has
> been in an extreme back-order situation for the last two years. It was
> developed in 1963 by Schering-Plough. Clint Pharmaceuticals has
> distributed many doses of this product over the last 15 years without
> even one incident of adverse reaction or fatality reported to our
> company.
>
> The anesthesiologists or pain management physician uses Celestone
> Soluspan in epidural injections to reduce the pain in their patients.
> Celestone Soluspan has not been available due to complications with
> the FDA and Schering-Plough, the manufacturer.
>
> The lack of access, of patient access to Celestone Soluspan, has
> spawned fatalities and adverse reactions across our country. These
> adverse events are due to the pain physicians having to resort to
> using compounded steroids in treating their patients.
>
> I have Exhibit B, a list of various sightings where these fatalities
> and adverse reactions have been reported.
>
> We have, however, no idea how extensive these incidents are because
> compounding pharmacies are not regulated. They do not have to report
> adverse reactions, compounding pharmacies do not have to comply with
> good manufacturing practices.
>
> There are only two other commercially available long-acting repository
> steroid suspensions available to the interventional pain specialists.
> One is Kenalog and the other is Depo Medrol, which I showed to you
> earlier.
>
> Many times these commercially available steroids are unaccessible to
> the interventional pain physician. Kenalog, for example, has benzyl
> alcohol. Benzyl alcohol as a preservative is known as a neurotoxin.
> Depo Medrol contains polyethylene glycol, which has been implicated in
> arachnoiditis.
>
> DR. KATZ: I need to ask you to finish your sentence and your time is
> up.
>
> DR. EBEL: I am requesting that you put this product on an emergency
> use for the pain interventional physician as you have with the Ob-Gyn
> patients as this product is being used with the Ob-Gyns in fetal lung
> maturation and is available to them. I would like to have this product
> available to the interventional pain physician.
>
> DR. KATZ: Thank you.
>
> Dr. Van Zee.
>
> DR. VAN ZEE: My name is Dr. Art Van Zee. I have no financial
> disclosures. I guess I should disclose that I grew up in Nevada.
>
> I am a general internist that has practiced the last 27 years in a
> small coalmining town in Southwest Virginia. What has brought me to
> these issues has been the OxyContin abuse problem.
>
> It would be hard to overstate the devastation that this has brought to
> Central Appalachia and now a number of other areas of the country.
> There are literally tens of thousands of new opioid addicts in Central
> Appalachia stemming from the use and abuse of OxyContin. Many of these
> are good kids from good families who recreationally used OxyContin and
> became rapidly addicted.
>
> Most of the OxyContin issues have to do with chronic noncancer pain
> issues. The noncancer pain market, if you will, constituted 85 percent
> of the total opioid market in 1999, and Purdue Pharma has aggressively
> promoted opioids in general, and OxyContin in particular, for chronic
> noncancer pain.
>
> What do we know about the risks and benefits of opioids in chronic
> noncancer pain?
>
> The risks of diversion have certainly been much higher than expected
>
> This map is from IMS Health that documents OxyContin prescriptions per
> capita, highest and lowest states in the year 2000. The thing that
> this speaks to I think and some of the subsequent slides, graphic
> slides, to some of the questions raised about regional variation,
> variability of OxyContin abuse.
>
> For those of you familiar with the OxyContin abuse problem, if you
> made a slide of those areas that were affected by that problem in the
> year 2000, it would virtually superimpose over these areas here.
>
> I want you to note that Virginia appears as a normal area, normal kind
> of prescribing area for OxyContin.
>
> If you look at more detailed data, and this data comes out of the
> ARCOS system through the DEA\'s Office of Diversion Control where they
> are able to track opioid distribution down to the retail level, one
> can see on this slide, the year 2000, OxyContin distribution per
> 100,000 population, the red being over national average prescribing.
>
> You can see this remarkably high area in Southwest Virginia. This is
> all Southwest Virginia area and this is where we have had extensive
> OxyContin abuse problems, and it is not just that this area is a
> higher prescribing area, but a very higher prescribing area.
>
> These counties range in OxyContin prescribing anywhere from 300 to 600
> percent higher than national averages.
>
> Other states involved in the Central Appalachian OxyContin problem
> have similar demographic information in terms of high OxyContin
> prescribing and high use. East Kentucky, as you have heard about
> today, has had a terrible problem.
>
> Maine, West Virginia, Alabama, the story is much the same, and, to me,
> this information would suggest that the high availability of OxyContin
> was associated with high abuse rates and, not surprisingly, reinforce
> the old idea that a highly abusable drug, if widely available, will be
> widely abused.
>
> What do we know about the risk of addiction for treating chronic
> noncancer pain? We don\'t have a definite answer about that. There are
> some studies that looked at the risk of addiction in treating acute
> pain setting, and those were somewhat reassuring.
>
> There are a number of studies that looked at prescription opioid abuse
> behaviors, and that is not to be equated with addiction, but they can
> certainly run around together and these are oftentimes an indicator of
> addiction problems.
>
> Dr. Portenoy, at this same committee hearing a year and a half ago,
> said that quite frankly we really don\'t know what the risk of
> addiction is in treating patients with opioids for chronic,
> nonmalignant pain.
>
> What are the benefits of using opioids for treating chronic,
> nonmalignant pain? Again, there is very limited data on this. In the
> handouts, I referenced eight studies that were prospective,
> randomized, double-blind, placebo-controlled studies lasting at least
> four weeks in duration, and if you take those studies as a whole, you
> will see that the efficacy is certainly there, but it\'s a very thin
> to modest amount of efficacy, and the functioning is essentially not
> improved.
>
> DR. KATZ: Dr. Van Zee, I have to ask you to wrap it up.
>
> DR. VAN ZEE: So, in conclusion, I would say there has been great harm,
> pain, and suffering from the OxyContin abuse problem in areas that
> have been affected. Its high availability seems to correlate with high
> abuse. From my point of view, it is very problematic in a risk-benefit
> analysis of opioids in chronic, nonmalignant pain when we really
> don\'t know what a lot of the risks are involved including addiction
> and diversion.
>
> Thank you.
>
> DR. KATZ: Thank you, Dr. Van Zee.
>
> Siobhan Reynolds is next and Gregory Walter will be after her.
>
> MS. REYNOLDS: Good afternoon. I am Siobhan Reynolds, Executive
> Director of Pain Relief Network in New York City. We don\'t have any
> relationship with pharmaceutical companies of any kind.
>
> We are a national patient and physician advocacy group dedicated to
> making pain care available to Americans. I would like to tell you, if
> I might, how I came to sit before you today.
>
> I married a man, Sean Greenwood, who developed severe chronic pain as
> a result of a congenital connective tissue disorder. We were married
> for 11 1/2 years, we had a son, and I continued to care for him.
>
> As a result of the damage he and our family suffered because we were
> unable to find pain care, I became an advocate on behalf of all
> Americans in pain. I became familiar with the inner circle of cutting
> edge pain care and was invited to participate in an internet listserv
> discussion on the issues confronting physicians who treat pain.
>
> One by one, I watched as several of our most prominent members were
> arrested and charged with murder or subjected to accusations of
> violating the Controlled Substances Act. I knew, as I watched this,
> that something was going terribly wrong.
>
> I am trained as a film-maker, so I set out with my camera to find out
> what the stories were behind the attacks. What I found will soon be a
> film, but it also brought me before you here today.
>
> In my travels, I came across Dr. Deborah Bordeaux as she was about to
> stand trial in the trial that this lady was referring to, in South
> Carolina, for writing prescriptions for pain medications outside the
> course of professional practice and without legitimate medical
> purpose.
>
> I sat alongside here and two other doctors tried on similar charges. I
> was shocked and dismayed to learn that the Justice Department was
> bringing out-of-date, anti-scientific and prejudicial testimony into a
> U.S. courtroom in the hopes of convincing the jury that by prescribing
> medication in conformity with the actual up-to-date standard of care,
> the standard I am familiar with, that the doctors had done something
> shameful, something unspeakably wrong.
>
> I have since watched the U.S. bring such cases all around the country.
> I began PRN and hired nationally renowned counsel to take up Dr.
> Bordeaux\'s appeal, partly because I wanted to save this innocent
> woman from federal prison, but also because I wanted to figure out
> what was going on here. How could it be, I asked, that in an area of
> medicine so central to the physician\'s role, that of relieving
> suffering, could find itself so thoroughly overwhelmed, so unable to
> develop its own methods and clinical practices in the communities, as
> any other area of medicine is allowed to do.
>
> As it turns out, the red flags that the government uses to determine
> if a doctor appears to be diverting drugs rather than practicing
> medicine are, for all intents and purposes, identical with the markers
> I or the healthcare professionals I know would identify as signs that
> good progressive medicine is being practiced.
>
> In other words, what we have is a perfect storm created by the
> collision of the development of progressive pain care with the
> application by Ashcroft\'s Justice Department of a now hopelessly
> out-of-date Rosen Rules.
>
> As a result, hundreds of physicians have been misidentified as being
> in violation of the Controlled Substances Act and have borne the full
> brunt of Justice Department drug prosecutions aided by determinant
> sentencing laws that have become so draconian that even the Supreme
> Court Justices Rehnquist and Kennedy have moved to speak out against
> them.
>
> Physicians all over America have been induced to take plea deals or to
> walk away from medicine rather than face what Dr. Bordeaux currently
> faces. Having been convicted by a lay jury of violating the CSA, Dr.
> Bordeaux\'s OxyContin prescriptions, 270 pills in total, were weighed
> up as though they were heroin, and the probation department has
> recommended that she spent 100 years in prison.
>
> Since the committee, this committee cannot be moving to further manage
> the risk of Palladone, as a result of objective evidence of harm,
> because the only evidence we have actually disproves the DOJ\'s claims
> of hundreds of deaths summarily, and you cannot be concerned on the
> basis of any finding by any court that Purdue Pharma has been
> negligent, because they have been beating all these claims against
> them without exception, I must conclude, therefore, that your
> perception of the risks posed by Palladone is created at least in part
> by the astonishing increase in physician prosecutions recently
> reported by the Justice Department.
>
> I am here to tell you that a terrible misunderstanding has occurred
> here and the public health has been inestimably damaged. All over
> America, doctors have simply put down their pens, patients in pain
> have returned to their beds or committed suicide. The suffering and
> destruction of innocent life is unimaginable.
>
> PRN is therefore calling for you to suspend your cooperation with the
> DOJ and to stand solely for your primary commitment to safeguard the
> public health. The public and the compassionate physicians have been
> badly let down by our Federal Government, a Federal Government which
> seems to have lost its way.
>
> We hope you will join us in our call for an open and frank
> congressional investigation in what has happened here before you
> resume your collaboration with the DOJ.
>
> The damage done will only come to be known as we uncover the deaths
> and listen to the stories the American, the stories the American
> people, the people have to tell.
>
> You can find\--
>
> DR. KATZ: Ms. Reynolds, you need to wrap up.
>
> MS. REYNOLDS: You can find our web site at painreliefnetwork.org and
> thank you very, very much.
>
> DR. KATZ: Thank you.
>
> Gregory Walter is next and then Mary Baluss.
>
> DR. WALTER: Good Afternoon. I just have a few things to say. I am an
> emergency physician in South Georgia. I have been an emergency room
> physician for 20 years. My wife of 10 years has been a chronic pain
> patient.
>
> I think it\'s appalling the way we treat our chronic pain patients in
> this country. I have sat in emergency rooms with her for five hours to
> have her declared a drug addict, a drug-seeking individual. I have had
> her denied care time and time again.
>
> I have had a personal perspective that not too many people have had.
> I, for 20 years, have had drug-seeking people come to me, and I have
> had to make the decision whether they are diverter or not, and I have
> done this to the best of my ability with all the skills I possess.
>
> I have also worked in this pain clinic in South Carolina for six
> months, which the DOJ has declared a hell hole, and I just wondered
> when the DOJ was going to tell you that there were only two pain
> clinics in all of South Carolina, so the patients have to drive for
> four hours to get pain medications.
>
> Then, I was wondering when they were going to get to the fact that
> after they closed the two, not one, pain clinics in South Carolina,
> how the numbers dropped, but then the whole entire State of South
> Carolina has no place to go.
>
> I thought the DEA was going to tell us that they were going to make
> sure the patients had a place to go, but when they closed those two
> clinics and confiscated all the patients\' records, where were these
> patients to go?
>
> That\'s all I wanted to say.
>
> DR. KATZ: Thank you, Dr. Walter.
>
> Mary Baluss and next will be Bruce Canaday.
>
> MS. BALUSS: Good afternoon. My name is Mary Baluss. I am the Director
> of the Pain Law Initiative. I am also speaking today on behalf of the
> National Foundation for the Treatment of Pain. I am also the Chairman
> of the Maryland Pain Initiative.
>
> I, myself, have received a grant from Purdue that allows me to buy two
> medical journals a year, and that\'s it, and as far as I know, and I
> just don\'t know for sure, there is no industry funding for the
> National Foundation for the Treatment of Pain.
>
> However, I am here today to talk to you a little bit in reactive mode.
> I would say that my message to you is do not restrict the availability
> of OxyContin to particular specialties. The specialty of the
> anesthesiologists doesn\'t want to use OxyContin because, in part,
> procedures are so much more profitable.
>
> The other specialties, which are not so overtly associated with pain
> management, see the great bulk of American patients, and I assure you
> that in the rural areas in small towns, they see the people with
> serious chronic pain.
>
> So, I would say please do not restrict the specialties. Doctor
> education at every specialty level is a wonderful idea. It should be
> based on clinical experience and clinical data, and not on scare
> stories.
>
> Do not restrict OxyContin to severe pain even if you can figure out
> what that means. Pain is subjective, it takes everybody, as we have
> seen data today, it takes everybody differently, our little bundles of
> nerves react differently to different stimuli and to different pain
> medications.
>
> By the time a person gets to the privilege of being tried on opioids,
> they have usually had or been asked to have every intervention that
> could possibly be dealt out. The ones who haven\'t had those
> interventions are the people who can\'t afford it, and this is another
> reason not to restrict the medical pain management modality is because
> the poor people cannot afford your procedures, and they are the people
> who worked in the coal mines and the other aspects of Appalachia, and
> they hurt, and that suffering is so palpable.
>
> I get a lot of phone calls and I don\'t charge my clients who are pain
> patients, and I don\'t charge the doctors that I help out, but I get
> calls almost every day and sometimes several day which basically say
> my doctor dumped me, what am I going to do. Where do you live? Well, I
> live in a little town near Des Moines or a little town near Columbia,
> South Carolina, or a little town near New Orleans.
>
> Some of then live in big towns, but mostly they live in little towns,
> and their doctors have decided it\'s not worth the trouble, it\'s not
> worth the fear of investigation, it is not worth hassling with
> pharmacists. This is why we need doctor education, not to reduce the
> prescribing, but to make it as intelligent and as clinical as
> possible.
>
> Now, the DEA\--and I didn\'t come here to mix it up with the DEA
> today, but they sort of started it\--the DEA\'s Risk Management
> Program is based on two things\--three things. One is the
> criminalization of prescribing to people who are lying to you.
>
> Another is the expectation of perfect prognostication on the part of
> any doctor, so that he knows when he is being lied to.
>
> Thirdly, they have conflated the notion of legitimate medical purpose
> with the notion of illegitimate medical procuring on the part of
> would-be patients, and you can\'t do it that way.
>
> We need more data on outcomes, we need more research, we need more
> funding for drug abuse, for people who are addicted, but we don\'t
> need the DEA\'s suggestions that were made today.
>
> Finally, Dr. Willis started this. I, like Ms. Reynolds, was very close
> to and sat through the entire trial of South Carolina doctors. The
> only people testifying against those doctors were themselves plea
> bargaining felons.
>
> The doctor who testified against them was a specialist in nothing. He
> had no board certifications, never taken a pain management
> certification, and I know you are going to tell me to sit down. So,
> thank you.
>
> DR. KATZ: Thank you, Ms. Baluss.
>
> Next is Bruce Canaday and after that Arthur Horn.
>
> DR. CANADAY: Thank you for the opportunity to present the views of the
> American Pharmacist Association.
>
> I am Bruce Canaday, clinical professor with the University of North
> Carolina, and Director of Pharmacotherapy for the Coastal Area Health
> Education Center in Wilmington, North Carolina. I am also a member of
> the APHA Board of Trustees and appearing today on behalf of the
> Association.
>
> In the interest of full disclosure, I have on occasion been involved
> in project funded by pharmaceutical manufacturers, and APHA commonly
> partners with federal agencies, consumer groups, the pharmaceutical
> industry, and others to develop educational tools for pharmacists and
> consumers.
>
> Neither I nor the Association received any funding to participate in
> today\'s meeting. The views I am presenting today are solely those of
> the Association and its membership.
>
> As the medication use experts in the healthcare team, we would like to
> share our experience with risk management programs, offer our
> perspective on program design, and provide recommendations on the
> development of risk management programs for opiate analgesics.
>
> Before you can discuss the design of risk management programs, there
> is a few fundamental questions to be addressed. First, what is the
> specific risks identified, is the risk to manage the potential of
> adverse events or contraindications, or is it product abuse and
> diversion? Very different things.
>
> It is equally important to establish the metrics of success. If the
> risk is diversion, does success mean a reduction in diversion or zero
> diversion, and what numerator do you use, what denominator?
>
> These questions should be at the forefront of considering risk
> management programs for any product. Pharmacist participation in risk
> management programs have grown significantly in recent years. Despite
> the additional steps that participation requires, we would rather work
> to mitigate product risk than lose a tool in our armamentarium for
> curing patients and helping them.
>
> Patients must not lose access to opiate analgesics because of failure
> to reduce risk or prevent misuse. While pharmacists want to
> participate in risk management programs, our experience has not been
> very positive to date.
>
> We are often not provided with the opportunity to help shape the
> programs we are then responsible for implementing. In some cases, in
> fact, pharmacists are excluded from participating all together. APHA
> has significant concerns with these restrictive distribution programs.
> Any pharmacist should be allowed to participate in a risk management
> system.
>
> While it is understandable that participation may require that the
> providers meet certain requirements, providers who meet them should be
> allowed to opt in the program, and not be automatically excluded.
>
> To increase the effectiveness of risk management programs, pharmacists
> must be involved both in the development and implementation. The
> current product-by-product approach to risk management is frankly a
> bit of a morass.
>
> The risks are identified with a product, a new program is developed to
> address that risk which may bear little or no similarity to currently
> existing programs. APHA strongly supports utility or a systems-based
> approach to risk management, this approach, create a prototype system
> that includes standard tools.
>
> As products are identified that require special attention, the program
> is built with the appropriate tools from the prototype system. This
> would provide consistency, limit administrative burden, increase
> program efficacy and effectiveness, and allow providers to place
> greater focus on patient care.
>
> As you discuss opiate analgesics, I would like to highlight three
> areas for your consideration. First, when preparing for this meeting,
> it was unclear if the Agency is seeking a new program for one new drug
> product, or group of similar products, or an entire class of drugs.
>
> We have concerns if the Agency targets one specific pain relief
> product for a risk management program when other products have similar
> risk. If all the products in class have similar risks, the risks could
> be managed in a consistent manner, otherwise, providers will migrate
> to products of similar risk with frankly less hassle.
>
> Second, if the goal is to limit diversion, it must be very carefully
> considered. Opiates are under the spotlight already. A program to
> reduce diversion could not only restrict access to appropriate pain
> medications, but really significantly compromise the entire system.
>
> Finally, controlled substances are subject to state oversight and
> federal DEA rules. You need to be sure that we are not in conflict
> with existing laws. The agency should consider what diversion programs
> are already in place or under consideration. I know Florida and
> Virginia are putting together their own programs, which are going to
> make it a bit challenging to deal with another set of regulations.
>
> We welcome the opportunity to work with the Agency. We recommend that
> you consider a utility approach in risk management, managing products
> with similar risks or similar systems to help providers navigate the
> system, and to allow us to focus on what we should be, the patient and
> appropriate medication use.
>
> Thank you.
>
> DR. KATZ: Thank you.
>
> Would anybody from FDA care to address the question about whether the
> FDA is seeking risk management, the device for a single drug or for
> the entire class of drugs?
>
> DR. RAPPAPORT: This particular meeting is about Palladone, it\'s about
> a risk management plan for Palladone. There is a possibility that this
> could be expanded to apply to other similar products in the future, as
> well. That is not the topic of this specific session.
>
> DR. KATZ: Arthur Horn and next is Jan Towers.
>
> DR. HORN: Good afternoon. My name is Arthur Horn. I am a physician in
> Hagerstown and Frederick, Maryland, just down the road.
>
> I have come today because Congressman Wolf asked me to come and share
> some of my feelings about narcotic therapy. My practice consists of
> chronic pain management. I have been doing so ever since I came to
> Maryland back about 14 years ago.
>
> I don\'t have to bestow the virtues narcotic therapy has really
> changed over the past couple of years, particularly the last 10 years.
> Patients have definitely benefited from that. There is an improvement
> in function, there is certain more functional standpoint that we are
> able to find with these individuals.
>
> But one of the tools that we have used, OxyContin is a double-edged
> sword. Although it works well, well tolerated initially, has been a
> problematic drug particularly over the past couple of years with all
> the notoriety that we have seen.
>
> I would like to make some suggestions as a doctor in the trenches, you
> know, a doctor who basically treats patients every day including my
> daughter, she has a complaint every day also.
>
> I am very concerned about the increase equivalent amount of morphine
> that patients receive on a daily basis, and that clearly has been
> escalating, and not only has that been escalating as newer products
> have come out, but as these patients stay on longer as your tolerance
> builds up, sometimes they can be receiving whopping doses of narcotic
> therapy on a daily basis.
>
> That leads me to the second problem with OxyContin, which is the
> street value. I went ahead and I went to a pharmacy, and I asked to
> weigh out 40 mg tablets one ounce of OxyContin. That turned out to be
> 210 tablets. Retail cost was \$1,040. When I calculated it out on my
> little calculator, that came out to 2 1/2 ounces of gold.
>
> When I converted that to the traditional sale of OxyContin, which is
> \$1.00 a milligram, that came out to \$8,400 for that one ounce of
> OxyContin, which equals 21 1/2 ounces of gold. Again, this is part of
> what I think is the motivation for some of these diverters.
>
> Once again, we do want to treat these individuals, they have clearly
> responded favorably, the people that take the medication
> appropriately, but when you are looking at such a marked profitability
> in terms of a single one prescription, it is really an attractive
> nuisance as far as I am concerned, and, well, once again, leads to
> further problems.
>
> In addition, I think most of the doctors that treat chronic pain and
> that prescribe chronic opioid therapy really are effective at what
> they do. They really try their best, they try not to give patients
> medications for abuse or diversion, but as we saw, there is a small
> number of doctors that really stick out, that are really running
> prescription mills, and there are some doctors that just aren\'t as
> careful as they should be.
>
> I am concerned about the doctors in the middle, the ones that may
> suspect a patient is abusing medication, but are not willing to really
> do anything about it. Those are the ones that really need to be
> watched, because I think they are very pervasive throughout the entire
> medical community.
>
> My suggestion is, as was brought up, a bar code on tablets or a tagon
> \[ph\] put inside. I would like to see that traced back from the
> apprehended products on the street, and find out where that came from,
> find out whether it was stolen from a truck or which doctors and which
> patients were involved.
>
> The reason why is because we really have to control this to get some
> effective use of this medication without fear of reprisal, but on the
> other hand, we have to take these bad guys off the street.
>
> Another issue, and I would only like to throw it out, I don\'t know
> how realistic it is, that perhaps when patients take a medication,
> such as OxyContin, which has a 20 to 30 percent immediate release
> within the first two hours, this may represent a public safety issue
> in terms of driving, you know, operating equipment and things like
> that, and that certainly is another consideration to be given.
>
> Ultimately, in conclusion, I believe that OxyContin has been very
> helpful, but on the other hand, it is a problematic drug, which does
> have its problems in terms of euphoria and this large amount of
> narcotic therapy.
>
> I think if we can identify the abusers that are involved or the people
> that are helping this, I think we could make a difference in continue
> to improve our patients with chronic pain\'s lives.
>
> Thank you.
>
> DR. KATZ: Thank you, Dr. Horn.
>
> Jan Towers and next with be David Joranson.
>
> DR. TOWERS: My name is Jan Towers. I am the Director of Health Policy
> for the American Academy of Nurse Practitioners. I have no direct
> financial relationship with any pharmaceutical companies, but our
> organization does accept unrestricted educational grants for many of
> our activities from a variety of pharmaceutical companies.
>
> The American Academy of Nurse Practitioners is the full service
> national organization representing advanced nurse practitioners from
> all specialties. Advanced practice nurse practitioners practice in a
> variety of settings where it is necessary to prescribe and manage
> opiate analgesic drug products for the patients under their care.
>
> These sites range from pain management clinics, hospice and oncology
> practices to acute care facilities and primary care practices. Nurse
> practitioners also practice in settings where they are working with
> patients to deal with addictions associated with misuse and abuse of
> these same drugs.
>
> The comments made here are considered in the perspective of nurse
> practitioner experience with the management of patients in all of
> these settings.
>
> As we review materials to be used in the consideration of a framework
> for a risk management plan for extended-release opiate analgesics,
> there are a number of SDA, risk management activities that we feel are
> particularly applicable to authorized prescribers and dispensers of
> these drugs.
>
> While the DEA has responsibility for dealing with the illicit use of
> these drugs, we feel the FDA\'s responsibility centers around the safe
> and effective use of these drugs in legitimate patient care settings.
> In this context, we would suggest the following.
>
> First, in addition to clear product labeling that includes
> descriptions of the drug structure\'s actions and interactions, side
> effects, contraindications, documented studies in dosing, we encourage
> the inclusion of high-quality patient education information focused on
> increasing patient knowledge and hence, appropriate compliance by
> patients for whom these medications are prescribed.
>
> Second, we endorse the concept of additional education and outreach to
> healthcare professionals and suggest that this concept be extended to
> consumers, that is, patients, as well. Studies have shown that the
> most effective treatments are those where providers and patients are
> well informed and share in the therapeutic process.
>
> In the area of tool development, we would suggest that contributions
> to the development of tools be broader than what is in your document
> that you have today, physicians, pharmacists, patients, and insurers.
>
> We further suggest that the target groups be broader than physicians
> and pharmacists as listed in the FDA concept document. Advanced
> practice nurse practitioners, for instance, can make a viable
> contribution to the development of educational and outreach tools
> focusing on these drugs.
>
> We suggest that you seek their input in your deliberations and in the
> development of processes adopted by the FDA to assure the safe and
> effective use of these medications. With their focus on the total
> patient and his or her environment, and the provision of care to
> patients with acute and chronic pain, and with their additional
> expertise in patient education and counseling, input from advanced
> practice nurse practitioners regarding these issues as they apply to
> both patients and providers would be an asset to the development and
> implementation of risk management programs centering on these
> medications.
>
> In addition, we would caution you not to take steps that would limit
> needed patient access to these medications prescribed and dispensed by
> authorized prescribers and dispensers in all healthcare environments.
>
> We would suggest that educational and outreach programs also be
> explored and developed to assist providers, patients, and patient
> support systems in recognizing and managing patients with addiction
> problems, and we endorse the evaluation process suggested in the
> concept paper.
>
> While problems have arisen with the use of opiate analgesic drugs, the
> use of these medications, particularly in the management of chronic
> pain, has demonstrated their worth. We suggest that a well-informed
> provider-patient and public population can facilitate the safe and
> effective use of these particular drugs.
>
> We thank you for the opportunity to speak with you today. The American
> Academy of Nurse Practitioners is interested in working on these
> projects with you and with the Food and Drug Administration. You have
> our contact information.
>
> Thank you.
>
> DR. KATZ: Thank you.
>
> David Joranson, you are up, and Daniel Carr, you will be the next and
> final speaker.
>
> DR. JORANSON: My name is David Joranson. Our published work has been
> supported by grants from the Robert Wood Johnson Foundation. Our group
> at the University of Wisconsin has also received unrestricted grants
> from Purdue, Jansen Pharmaceutical, Ortho-McNeil, and I have received
> some honoraria from time to time for occasional lectures. No company
> paid for my trip here today.
>
> The title of my talk is Use the Principle of Balance to Evaluate Risk
> Management Strategies for Opioid Analgesics.
>
> Mr. Chairman, committee members, the task of developing risk
> management strategies for approved opioid analgesics is essential to
> good public health policy. The appropriate medical use of opioid
> analgesics is absolutely essential for many patients because adequate
> pain relief restores quality of life and saves lives.
>
> However, there are still many barriers to the appropriate medical use
> of opioids. Opioids also have an abuse potential. Drug abuse destroys
> lives and diversion of prescription pain medications from legitimate
> medical channels to illicit uses should be prevented, but efforts to
> prevent the abuse of opioid analgesics should not interfere with their
> use in legitimate medical practice and patient care.
>
> This is a principle called balance, and achieving the right balance
> between these two public health objectives, that is to say, preventing
> abuse and ensuring patient access is the subject of my statement and I
> think the mission of the Committee, as well.
>
> FDA and the Committee can use the principle of balance to evaluate
> various risk management strategies. There are two tests for balance.
> One is that the strategy should have a high potential to prevent
> diversion or abuse, and, two, that the strategy should have a low,
> perhaps zero, potential to interfere with legitimate medical practice
> and patient care.
>
> For example, balanced strategies to address diversion and abuse would
> include measures to prevent pharmacy theft, to identify employees who
> divert medications, to identify doctor shoppers, making sure to
> distinguish them from inadequately managed pain patients, to educate
> physicians about how to identify at-risk patients or to formulate
> products to reduce their abuse potential.
>
> These strategies are balanced because they address the sources of
> diversion and abuse directly without interfering in legitimate medical
> practice or patient access to needed medications.
>
> In contrast, unbalanced approach would be physicians who stop
> prescribing to all patients or who refer all their patients to
> specialists, pharmacists who refuse to stock needed medications,
> insurance companies that restrict reimbursement or agencies that
> restrict the amounts that physicians can prescribe to patients.
>
> These are unbalanced because they are not aimed directly at the source
> of the problem, and they have a clear potential for interfering in
> medical practice, interrupting patient access to pain relief, and
> increasing the burden on health professionals and patients.
>
> As the Committee evaluates risk reduction strategies, I ask that you
> consider the extent to which crime is the source of the opioid
> analgesics that are abused. Large and as yet unknown quantities of
> prescription pain medications are diverted each year, are abused, and
> thus, contribute to the drug abuse statistics that you study.
>
> This particular chain of events begins with criminal rather than
> medical or patient behaviors. I am referring to pharmacy theft,
> forgery rings, doctor shopping by non-patients who feign painful
> illnesses in order to obtain prescriptions.
>
> It is important to note that in the 1980s, at the urging of the
> country\'s pharmacists, Congress made pharmacy theft of controlled
> substances a federal criminal offense, however, little is known about
> how this law is enforced in the country.
>
> It is important for the Committee to realize that risk management
> strategies that you may develop for use particularly within the
> healthcare system are independent of, and may not affect, the abuse
> levels of medications being diverted by criminal activities. In fact,
> statistics are available to quantify diversion from pharmacy thefts,
> and I would urge the Committee to obtain these data and factor them
> into your understanding of the numerators and the denominators.
>
> We respectfully recommend that FDA and the Committee use the principle
> of balance to evaluate risk management strategies. A balanced approach
> is consistent with good medicine where we aim to do no harm and where
> we avoid cures that are worse than the disease.
>
> A balanced approach is also completely consistent with international,
> federal expectations of what amounts to good drug regulation.
>
> I have attached a bibliography to my statement and I will be pleased
> to provide any other information that the Committee may require.
>
> Thank you.
>
> DR. KATZ: Thank you. It may be worth pausing for a second since Mr.
> Joranson has proposed a relatively simple lens through which we can
> look at any proposed risk management strategy, and since that is what
> we are doing for the next day or so, the strategy being to simply look
> at to what extent they are likely to impact upon the problem we are
> trying to impact on, namely, diversion and abuse, and then to what
> extent they may interfere with normal medical practice.
>
> Does anybody have any questions for Mr. Joranson about that principle
> of balance and about his experience in implementing that policy and
> evaluating regulations? Russ.
>
> DR. PORTENOY: Just to clarify a point. The aspect of balance that
> relates to the negative side, what we would like to try to deal with
> in terms of the positive outcome of risk management program relates to
> reducing diversion, reducing or limiting the adverse consequences of
> addiction, and then there is this gray area of misuse where physicians
> who don\'t have adequate skills may use these medications
> inappropriately.
>
> Several of the speakers have addressed that and obviously, for those
> of us who are pain specialists, it is a very problematic thing because
> we try to educate physicians in order to treat pain more effectively,
> to use these drugs more effectively, and it is quite clear that some
> physicians can be trained well and some physicians cannot be trained
> well, and the ones who are not trained well can become part of a
> problem, not only in relation to the problem of iatrogenic addiction,
> which is probably less common, but in the problem of not treating
> patients up to the standards of care where patients\' function
> declines and they don\'t do well as a result of continuing access to
> an opioid drug.
>
> We don\'t have much data about this, and I just wondered how you would
> put that piece of it, that issue of misuse, that gray zone in that
> misuse category, how you would put that into the balance equation.
>
> DR. JORANSON: Could you clarify what you are defining as misuse?
>
> DR. PORTENOY: Yes. What we would like to do, the lens through which we
> would like to evaluate the risk management program might be that we
> don\'t want to do anything that would reduce effective good medical
> care with respect to opioid therapy. We don\'t want any management
> program to make care less good.
>
> At the same time, we would like to target these risk management
> programs to try to reduce bad outcomes. So, under the bad outcomes, we
> have diversion into the illicit marketplace, we have the development
> of iatrogenic addiction.
>
> Do we also have a responsibility there to talk about the inappropriate
> use of opioid therapy by physicians who aren\'t adequately trained to
> provide these drugs or to monitor these drugs with sort of a broader
> negative than just the possibility of diversion?
>
> DR. JORANSON: Dr. Portenoy, I think the brief answer to your question
> is that good pain management is always going to require a large
> investment in education especially now that we know that very little
> about pain management was taught at all or perhaps not even accurately
> in past generations.
>
> We have got problems in knowledge to overcome, as well as teaching new
> knowledge. In some countries, doctors are so afraid of prescribing
> opioids that if you make them available to them, they won\'t prescribe
> them because they are too afraid.
>
> In this country, there are some doctors, as we know, that don\'t have
> that problem. My sense is that as a matter of public policy, education
> can be encouraged and perhaps at the state level it can be required as
> a continuing education piece as some states are, but it\'s
> experimentation at this point to learn what the effect of this kind of
> education will be on practice.
>
> But I don\'t think that we should rely on education to solve problems
> of deliberate misuse or diversion area activities. I think that is a
> job that we should focus on and clean up. We have done it a couple of
> times in past decades, and I don\'t think we should get those two
> things mixed up.
>
> If we can separate out the problems of diversion, target those and
> deal with them, it will be a lot easier to deal with improving the
> educational level of practitioners and many regulatory agencies,
> including the state medical boards, are eager to be involved in that
> process. About half of the state medical boards have adopted a policy
> statement that encourages increased education for any physician who
> makes pain treatment part of his or her medical practice.
>
> DR. KATZ: Dr. Passik, question?
>
> DR. PASSIK: We have a lot during the day today, a lot of statistics
> indicating, you know, curves going up, and as Russ said earlier, all
> we can really extrapolate from that is more availability, more abuse,
> but we haven\'t, other than Dr. Van Zee\'s comments in the open forum,
> really seen a big correlation between medical use and abuse,
> geographically or otherwise.
>
> I think that is one of the biggest problems we face is we don\'t know
> how much of it is coming. Of the 90 percent of diversion that was
> talked about the first thing this morning, we don\'t know how much of
> it is coming from medical use with pain patients.
>
> I wanted to ask David if he could amplify because he added another
> unknown, which is the whole issue of pharmacy theft, and I just
> wondered if he had any comments about that, because we have heard that
> 90 percent of the abuse happens there, but you have added yet another
> unknown, which is how much is being diverted from pharmacy theft as
> opposed from patients and doctors.
>
> DR. JORANSON: Well, obviously, the reason that you want to know how
> large that source is, is so that you can begin to factor out whether
> it is doctors and patients that are the problem, or whether it is
> criminals, so to speak, that are responsible for putting the drugs on
> the street.
>
> Of course, the short answer is that it is both, but we need to know a
> little bit more about the proportions, and I think this is also going
> to vary regionally. For example, I think DEA mentioned a high number
> of thefts in the Boston area, and that has been in the newspapers
> hundreds or more. It is possible to determine the amount of all
> prescription controlled substances that were stolen in those thefts.
> There is a form that all the pharmacists have to fill out, the DEA-106
> form, and presumably that data could be available and could be
> studied, and would add some perspective to the total quantities. These
> would be objective measures of diversion, not indicators. They are
> actual measures. That could happen for any pharmacy theft anywhere in
> the country.
>
> DR. PASSIK: Do we have that data and when was the last time it was
> available?
>
> DR. WILLIS: We could get that for you.
>
> DR. KATZ: Many people didn\'t hear that response, but the bottom line
> is that that data could be made available to the Committee.
>
> Dan Carr, you have got your five minutes in the sun.
>
> DR. CARR: Thank you very much, Dr. Katz, and the distinguished and
> erudite members of the Committee for giving me your attention.
>
> I recognize first that the issue of risk management is fraught with
> complexity and therefore, I have chosen only to identify two specific
> comments to leave you with amidst an ocean of greater complexity.
>
> I also point out that nobody paid for me to be at the meeting today.
> By coincidence, I had to be in Washington yesterday because the
> American Academy of Pain Medicine unveiled a new internet-based
> educational effort, a part of which encourages appropriate use of
> opioids, and tomorrow, the Institute of Medicine has a program on
> encouragement of clinical research.
>
> On the other hand, that educational program, and hence my airline
> ticket, was supported by Purdue very indirectly
>
> \[Slide.\]
>
> If we were able to deal with all the complex issues of risk, and we
> tackled them capably, we might produce an ideal world in which there
> is prospective identification and planning for patients who are both
> at risk of undertreatment of pain, as well as the adverse effects of
> such therapy.
>
> There would be prompt, perhaps even preemptive, individualized
> antinociceptive and palliative interventions including adjuvant
> medications. We would deliver effective treatments based upon rigorous
> evidence, and we would capture data about the effects and adverse
> effects in a standardized fashion.
>
> We would do so in a supportive climate with respect to policies,
> payment, and attitudes, and there would be recognition at the system
> level that the disease burden of undertreated pain far outweighs that
> of abuse, addiction, and diversion.
>
> One reference I could think about right off the bat that you could go
> to is the WHO global burden of disease web site to see numbers to
> support this. There would also be recognition at the system level that
> people have always and will always treat their pain by whatever means
> is available to them.
>
> There would also finally be recognition at the system level that the
> adverse effects of these treatments often preclude adequate pain
> control.
>
> \[Slide.\]
>
> Personal experience includes doing many systematic reviews and
> meta-analyses, some of these over the years funded by the government.
>
> \[Slide.\]
>
> Having looked at the evidence, there are a lot of problems with the
> evidence, and this evidence is evidence relevant to the formulation of
> policy concerning management of risk.
>
> Randomized, controlled trials are a tiny fraction of the literature
> and most of the literature is observational or describes a technique.
> There clearly are very important elements of data that would be
> important to formulate a rational risk management policy, not only for
> the single drug Palladone, but for all drugs which are lacking.
>
> Even in the randomized, controlled trials, a pervasive problem is
> underpowering. In fact, if one is assigned to pool the available data
> and construct a pooled efficacy estimate for various classes of drugs
> including opioids, it is an almost impossible task because of the
> heterogeneity of diagnoses, patients, and outcomes.
>
> There is a proliferation of instruments that have been employed, and
> that is for pain, and the picture is even worse for non-pain symptoms,
> such as fatigue.
>
> A 2003 systematic review commissioned by the American Pain Society on
> treatment of opioid side effects, which can be looked at in the
> Journal of Pain by McNicol, et al., was hampered by the lack of focus
> to date on the side effects.
>
> \[Slide.\]
>
> What the two points I wanted to make? Well, in formulating a risk
> management policy, one dimension of risk simply has to do with adverse
> effects. These are very important in the real world.
>
> Eric Mannheimer of the Cochrane Collaboration has pointed out that the
> assessment of effects and side effects in drug trials to date have
> proceeded as if they were two different dimensions or different
> universes.
>
> While for most of the effects, we capture these prospectively, seek
> them deliberately, and we use instruments that at least have some
> likelihood of reflecting consensus, thus far to date, the majority of
> trials, even randomized, controlled trials, have captured side effects
> only if volunteered or if prospectively, in an ad-hoc way.
>
> Given the importance clinically of side effects, and the fact that in
> the real world, they contribute to risk, consensus instruments and
> methods should be encouraged and possibly required.
>
> I know that I am echoing what many people around the table or in the
> audience have said, Mitchell Max, for instance, has a manuscript about
> this point, but I think this is an important opportunity in
> formulation of a risk management policy.
>
> Further, if instruments are standardized, this will allow pooling of
> data which is not currently possible.
>
> \[Slide.\]
>
> Now, looking at another dimension of risk, which is the societal
> dimension, I think we have heard from many of the speakers that
> discouraging clinicians from prescribing, controlled substances
> worsens the situation that is well documented of undertreatment of
> pain.
>
> Therefore, in the formulation of a risk management policy, adding to
> risk management burdens may increase the global aggregate societal
> risk from undertreated pain or the reliance upon unregulated
> analgesics. That might include street drugs, alcohol, or
> over-the-counter NSAIDs, which themselves carry considerable risk.
>
> I wanted to emphasize the point that the true systemwide risk is
> aggregated and it is distributed, much as one might imagine the
> process of treating pain as consisting of a flow of fluid, let\'s say,
> through a series of spigots. The spigots represent the choices of
> therapies, and if shut one spigot or make one element less available
> in a multi-spigot system, that has two effects.
>
> First, you increase the aggregate resistance slightly and you shift
> the flow to be through other spigots.
>
> So, I wish you would keep these two points in mind, and thank you for
> your attention.
>
> DR. KATZ: Thank you, Dr. Carr.
>
> Our next presentation will be from Ann Trontell. The open public
> hearing session is over. She is Deputy Director of the Office of
> Pharmacoepidemiology and Statistical Science at FDA, and will speak to
> us, giving us an introduction to the goals of risk management plans
> and also non-opiate risk management plans.
>
> After this presentation, we will have a break.
>
> **Existing Risk Management Plans**
>
> **Introduction: Goals of Risk Management Plans/**
>
> **Non-Opiate Risk Management Plans**
>
> DR. TRONTELL: Good afternoon. I am going to be providing a broad and
> general overview of FDA\'s experience to date in risk management
> programs and our evolving guidances on the topic of risk management.
>
> \[Slide.\]
>
> FDA\'s involvement with risk management is longstanding and derives
> from the Agency\'s role in weighing the risks of drug products along
> with their benefits in making decisions about drug approval.
>
> The nomenclature of risk management per se was probably introduced in
> 1999 when the FDA Commissioner released a report on managing the risks
> of medical products.
>
> \[Slide.\]
>
> With the passage of the Prescription Drug User Fee Act last year,
> FDA\'s role in risk management was formalized. The Agency was asked to
> develop three interrelated guidances on risk management and to do so
> by September 30th of next year.
>
> The topics for these three guidances were premarketing risk
> assessment, postmarketing pharmacovigilance and pharmacoepidemiology,
> and risk management itself.
>
> \[Slide.\]
>
> FDA gathered its preliminary thoughts in these three areas and
> published and presented concept papers on each in April of this past
> year, and solicited public comment. Draft guidances based upon these
> concept papers and the commentary received upon them will be published
> later this fall. There will then again be another opportunity for
> commentary.
>
> \[Slide.\]
>
> As a consequence, this presentation will be focusing both on FDA\'s
> experience with risk management, as well as the concepts that were
> articulated in the concept paper entitled \"Risk Management
> Programs.\" I hope you understand I am giving you a snapshot of what
> is a very rapidly evolving approach to drug safety by the Agency and
> our many partners.
>
> \[Slide.\]
>
> The Risk Management concept paper discussing risk management programs
> focuses on risk minimization efforts. These efforts are termed \"risk
> management programs\" in the concept paper. The risks are, in fact,
> identified using practices that are described in the other two PDUFA3
> documents on risk assessment in the premarketing and postmarketing
> areas.
>
> \[Slide.\]
>
> Important concepts, as Dr. Galson told you this morning, include our
> concept of safety, which is that it means for us, on balance, that
> beneficial actions of a product outweigh their harmful or undesirable
> side effects. It does not suggest that risk itself is absent.
>
> A risk management program was defined in the concept paper as a
> strategic safety effort to reduce risk and that that effort entailed
> one or more risk reduction goals and the use of one or more
> interventions or tools other than the package insert.
>
> The package insert, or PI, refers to the professional package insert
> or what you may know as FDA-approved labeling. This is not considered
> in the concept paper to be a formal risk management program in and of
> itself.
>
> \[Slide.\]
>
> As I stated, part of the definition of a risk management program is
> that it have one or more goals. The goals of a risk management program
> would, in FDA\'s concept paper, be tailored to a product\'s specific
> risk concerns and describe the ideal product use scenario or the
> desired end result of the risk management program.
>
> It would include a vision statement, if you will, of the optimal drug
> use scenario. Examples may illustrate this. For the drug product
> thalidomide, a known teratogen, the vision statement might be
> described as no fetal exposures. For clozapine, a product associated
> with agranulocytosis, the goal might be stated no agranulocytosis.
>
> \[Slide.\]
>
> In the concept paper, FDA discusses when a risk management program
> might be appropriate. The Agency describes in its concept paper that
> this might, in fact, occur whenever risk reduction needs emerge during
> a product\'s lifecycle, and this might, in fact, be initiated by a
> drug company\'s sponsor or by the Agency.
>
> The language proposed in the concept paper was in instances \"when the
> number or severity of a product\'s risks appears to undermine the
> magnitude of benefits in an important segment of actual or potential
> users.\"
>
> \[Slide.\]
>
> The challenge is how to assess, in fact, whether or not risks
> undermine benefits, and that will likely be much of the topic of
> further discussions here today and tomorrow.
>
> There is no simple formula that compares risks and benefits. They are
> measured in different units and they are of different types. As such,
> FDA stated in its concept paper that it anticipates case-by-case
> judgments will be made by the company\'s sponsor or by FDA on whether
> or not to develop, submit, or implement a risk management program.
>
> At the same time, the Agency acknowledges that for most drug products,
> that these will be handled sufficiently and well by the package insert
> without the need of a formal risk management program.
>
> \[Slide.\]
>
> Now, to turn to risk management program tools, which again were part
> of the definition, these we defined as a process or system intended to
> enhance safe product use by reducing risk. The choice of tools can be
> influenced by the severity of the risks, its reversibility or its
> rate.
>
> \[Slide.\]
>
> It may be useful for discussion purposes to talk about three
> categories of tools that can be used in current risk management
> programs. These include education and outreach, so-called \"guiding\"
> systems, and restricted access.
>
> \[Slide.\]
>
> First, education and outreach. As I stated previously, in the concept
> paper on risk management programs, the Agency specifically excluded
> the conventional professional labeling, or package insert,
> acknowledging, in fact, that this is the standard mechanism whereby
> the Agency, with drug company sponsors, communicates risks and
> benefits.
>
> Instead, education and outreach would describe those that go beyond
> the package insert, and might include, for example, the issuance of
> Dear Healthcare Practitioner letters or other public notices, training
> programs or offerings of continuing education, or patient-oriented
> labeling, such as medication guides or patient package inserts, or
> PPIs, which I will now describe.
>
> \[Slide.\]
>
> Medication guides are a form of FDA-approved patient labeling that
> have been regulated since 1999 with the reference given to you here.
> These patient labelings are, in fact, required to be dispensed by
> pharmacists with each prescription to a patient.
>
> They are intended primarily for outpatient prescription products that
> pose serious and significant public health concerns, and at the time
> this regulation became effective, it was anticipated that this form of
> patient labeling would be applied on average to 5 or 10 products on an
> annual basis.
>
> \[Slide.\]
>
> Medication guides have, as part of the regulations, the requirement
> that they meet one or more of the following criteria set within
> regulations, the first being that patient labeling could help to
> prevent the occurrence of serious adverse events; the second being
> where there might be serious risks associated with the use of a
> product or the patient should be informed in order to make a decision
> whether or not to initiate or continue use with that product.
>
> The third triggering criteria was instances where patient adherence to
> therapy and to directions was crucial to effectiveness, particularly
> for life-threatening conditions. Again, the regulations for medication
> guides set forth a standard format and content for these materials.
>
> \[Slide.\]
>
> Depending on how you counted, there are now approximately 13
> medication guide texts that cover approximately 22 different products.
>
> They cover a wide array of risks, and the risks are not in any way
> constrained by regulation. They include, but are not limited, to
> issues of hepatotoxicity risks, teratogenicity, abuse and diversion,
> and the potential for overdose.
>
> \[Slide.\]
>
> Patient packaging inserts, or PPIs, are yet another form of
> FDA-approved patient labeling with some important differences for
> medication guides. In the instances of products that contain
> estrogens, they are, in fact, required for distribution to patients,
> much like medication guides, but otherwise, PPI distribution is
> optional.
>
> In instances where PPIs may be used as the brief summary for direct to
> consumer ads, they are subject to FDA regulation, as listed in this
> slide.
>
> \[Slide.\]
>
> Many patient package inserts follow the medication guide format on
> FDA\'s encouragement that this format may well promote consistency in
> patient adherence with patient labeling.
>
> In fact, as many products are increasingly packaged in unit-of-use
> packaging where PPIs may be contained, they may function similarly to
> a medication guide and that each patient would receive a PPI.
>
> \[Slide.\]
>
> But to draw the distinction clearly, medication guides are required to
> be dispensed with medications to patients. For other than
> estrogen-containing products, PPIs are optional. In instances where
> generic products may enter the marketplace, they conform to the same
> labeling requirements as the innovator drug, and the medication guide
> requirements convey then, as well.
>
> \[Slide.\]
>
> Turning now to the second broad category of tools are those that we
> call systems that guide prescribing, dispensing, and use.
>
> The purpose of these systems is to assist individuals in following
> appropriate prescribing practices or stated in alternative terms, to
> make it difficult for individuals to forget important safety
> processes.
>
> These may use a variety of reminders or prompts.
>
> \[Slide.\]
>
> Examples of these might include the use of patient agreements,
> sometimes called informed consent, or practitioner certification
> programs. There have been a number of special conditions of dispensing
> that have been put into practice.
>
> These include special packaging, limitations on the supply of the drug
> product, or the inability to obtain refills. In some instances, check
> mechanisms have been put in place to assure that appropriate
> prescribing has taken place.
>
> \[Slide.\]
>
> An example of special packaging would be the drug product Lindane,
> also known as gamma-hexachlorocyclohexane. This product is now limited
> in its dispensing to one or two ounce aliquots due to the risk of
> seizures and death with overdose from this product.
>
> \[Slide.\]
>
> Yet another product, in this case having multiple guiding systems, is
> the drug product alosetron, known perhaps to some of you as Lotronex.
> For this product, there is a patient agreement. There is physician
> attestation to knowledge of the disease irritable bowel syndrome and
> of the attendant product risks in using this.
>
> The physician then obtains stickers which are affixed to prescription.
> These indicate then the physician\'s expertise, appropriate patient
> selection, and signing of the patient agreement.
>
> Pharmacists look for these stickers on prescription prior to
> dispensing. This system depends then upon individuals being aware and
> informed about its existence.
>
> \[Slide.\]
>
> Turning to the third category of tools are restricted access systems.
> These systems link drug product access to compliance with risk
> management program elements. An example would be the drug product
> clozapine, or the expression is \"no blood, no drug,\" the reason
> being that proof of adequate white cell count is necessary for
> pharmacists to dispense this product.
>
> Restricted access systems often limit prescribing and dispensing to
> selected healthcare practitioners and pharmacists and may require
> documentation of safe use conditions, such as laboratory tests or
> monitoring, before dispensing to patients.
>
> \[Slide.\]
>
> One example of a restricted access system is the thalidomide program,
> known as STEPS, standing for the System for Thalidomide Education and
> Prescribing Safety. I will be describing only a component of this, it
> is actually quite complex.
>
> But in the thalidomide system, this product is shipped only to
> pharmacists who are registered with the program, and these pharmacists
> can dispense the product only if the following conditions are met:
> that both the patient and the prescriber are registered with the
> program, necessary documentation is in place for that, and that, in
> fact, there is some receipt of centrally authorized information
> indicating both the provider and the patient have been compliant with
> the program features to assure that the product isn\'t given to anyone
> who is pregnant.
>
> \[Slide.\]
>
> In its concept paper, FDA set forth three considerations in the use
> and development of tools. The first was that stakeholder input be
> solicited on the feasibility and acceptance of the tools, and this
> would include all manner of prescribers, pharmacists, patients, and
> payors, and yet other parties perhaps we haven\'t named.
>
> The Agency also set forth the value of consistency in selecting and
> developing tools since we think it is important to look to existing
> and well-accepted tools to minimize confusion and burden upon the
> healthcare community.
>
> The Agency also indicated the value of evidence of past effectiveness
> of a tool in a similar product or in a similarly related safety
> objective in order again to make use of the most effective tools.
>
> One comment received by the Agency at its public meeting in April, and
> also in the written commentary that came after that, from the public,
> was that another important consideration needed to be stated
> explicitly. That was preserving patient access to the benefits of
> drugs at the same time that risks were minimized.
>
> \[Slide.\]
>
> It is important to make some mention here of Subpart H, which is a
> regulatory approval option available to FDA to be applied in instances
> where we have used surrogate endpoints or in instances where the
> Agency deems it important to have restrictions to ensure safe product
> use.
>
> Subpart H may include restricted access.
>
> \[Slide.\]
>
> However, restricted access or distribution can be done without
> approval under Subpart H approval provisions. Subpart H affords FDA
> the opportunity of more rapid product withdrawal if that should be
> necessary, and also gives FDA an opportunity to review promotional
> materials prior to their publication.
>
> \[Slide.\]
>
> The FDA concept paper on risk management programs states as one of its
> important principles that it feel risk management programs should be
> evaluated. The Agency feels it is important to measure the
> effectiveness and value-added of tools and to use this information to
> assess progress toward attaining goals and any changes in health
> outcomes that might be attributed to the program.
>
> It would also allow the modification, as necessary, of a risk
> management program to ensure that goals and health outcomes are, in
> fact, being met.
>
> \[Slide.\]
>
> In talking about evaluation, the risk management program concept paper
> has some overlap with the concept paper on postmarketing
> pharmacovigilance and pharmacoepidemiology. Active or targeted
> surveillance systems may, in fact, serve as means for measuring
> whether or not risk management program goals or objectives have been
> met and may, in fact, determine whether or not the overall risk
> management program itself is effective or needs modification.
>
> \[Slide.\]
>
> So, in summary, risk management programs, as they have been put into
> practice to date, and as FDA is stating its guidance to the industry
> over the coming year, these are sparingly applied interventions that
> have been intended to minimize identified risks and that are
> goal-oriented in terms of their purpose.
>
> Risk management programs use tools that are commensurate with the
> risks and benefits of the products, and that they merit evaluation.
>
> \[Slide.\]
>
> Let me summarize and expand the three categories of tools that I have
> described, the first being education and outreach. Education and
> outreach can take many forms, and the Agency and sponsors have had
> experience with these categories of interventions for many years. They
> can be general or targeted and applied to many drugs.
>
> They are perceived by many as being limited in their intrusiveness on
> conventional prescribing, dispensing, and use processes. Data on the
> effectiveness of these interventions is, in fact, limited, and the
> data that are available are mixed with evidence of low to moderate
> influence upon actual prescribing behaviors.
>
> \[Slide.\]
>
> The category of risk management program tools that I described as
> guiding systems are more limited in number than education and
> outreach. These are perceived to be moderately intrusive on
> conventional prescribing, dispensing, and use processes, and as yet,
> we do not have evidence on their effectiveness, but evaluations are
> planned for several of these programs.
>
> \[Slide.\]
>
> Lastly, the category of risk management program tools described as
> restricted access are, like the guiding systems, applied really to a
> small number of drugs and only a small number of systems are currently
> in practice.
>
> They have been applied to date for products that have limited
> therapeutic alternatives and which themselves are recognized to pose
> significant risks. As such, the product and user populations for these
> products is typically quite small.
>
> \[Slide.\]
>
> Restricted access programs, because they, in fact, do restrict access
> and distribution through pharmacists and prescribers, are perceived as
> being the most intrusive on prescribing, dispensing, and use.
>
> Because many of the participants in restricted access programs are
> registered, they are relatively closed systems and, as such, offer
> more easy opportunities to evaluate their success.
>
> To that end, the data that the Agency has received to date has
> supported their effectiveness in risk minimization in these
> specialized populations, but they do also show instances where product
> uptake has been slow and where there has been substitution of
> alternative products for products that have risk management programs.
>
> That concludes my remarks. I have a few minutes for questions if you
> like.
>
> DR. KATZ: Thanks very much. Dr. Wlody.
>
> DR. WLODY: I think one of the things that we could probably agree upon
> is that although we can\'t say how large a fraction of the problem it
> is, that some fraction of the inappropriate use of these opioid drugs
> may be due to lack of physician knowledge, and with that in mind, I
> think it is very interesting the case of alosetron where you mentioned
> that stickers indicating physician expertise have to be attached to
> the prescription before it is filled by the pharmacist, and I would be
> interested to know how that physician expertise is demonstrated, is it
> just the physician attestation of his knowledge?
>
> DR. TRONTELL: I will invite Dr. Raczkowski to add to my comments, but
> it is based upon physician attestation of the necessary knowledge to
> diagnose and appropriately treat irritable bowel syndrome, so there is
> no independent body assessing certification.
>
> There are, in fact, a few programs that do independently require
> certification. In the case of the drug product dofetilide, that is the
> case that a certain competency has to be demonstrated.
>
> DR. RACZKOWSKI: Yes, that is correct. The only thing I would add is
> that the physician\'s self-attestation also includes attestation that
> the physician is familiar with both the risks and manifestations of
> some of the serious side effects of alosetron and is familiar with how
> to treat those serious complications.
>
> DR. KATZ: Bob.
>
> DR. DWORKIN: It sounded to me like the two programs you described in a
> little bit of detail, the alosetron program and the thalidomide
> program, are ones that don\'t carry any penalties associated with not
> following these recommendations.
>
> Is that correct, that these are really structures without a penalty?
>
> Just a follow-on question, if that is true, is the DEA in a position,
> to the best of your knowledge, to institute similar programs that do
> have teeth, such that unless the program is adhered to, the individual
> doesn\'t have their DEA license maintained?
>
> DR. TRONTELL: The two programs that I described, the penalty, in fact,
> this probably may be a difficult term for me to apply, in the case of
> thalidomide, in fact, product access is not supposed to occur unless
> every step is done and documented. So, you might presume that the
> absence of the drug product being dispensed, the inconvenience or
> going back to, in fact, document the safe-use conditions could be an
> inconvenience, but no penalty is applied.
>
> In the instance of the alosetron program, there may be instances where
> individuals are unaware of the program where, in fact, a prescription
> may be filled without a sticker or a physician may, in fact, write a
> prescription without a sticker. Those are, in fact, being evaluated at
> this time to determine to what extent that may be a problem.
>
> Again, I will invite Dr. Raczkowski if there are any specific
> interventions related to any early signs that this may be having
> lapses in its application.
>
> DR. RACZKOWSKI: I have no additional comments.
>
> DR. KATZ: Dr. Cush.
>
> DR. CUSH: Could you comment on the utility of a registry system as a
> restricted access? I know those could be voluminous in what they
> collect, and they can also be limited, but nonetheless, have the same
> sort of effects as far as monitoring and tracking what happens to
> prescriptions and who they are given to, by whom, how many, and the
> outcomes of such prescriptions.
>
> DR. TRONTELL: My own perspective on registry systems, it varies in
> part with our own agency\'s experience. Registries may, in fact, be
> put in place for purposes of obtaining information rather than trying
> to direct use. In the case of pregnancy registries, that may, in fact,
> allow us to determine if inadvertent pregnancy exposure, so they are
> more information gathering than restricting, in fact, access to the
> program.
>
> Registry programs, mandatory registries, such as exist with
> thalidomide or for dofetilide, in fact, in practice, either because of
> the product or because of the registry itself, tend to be used on
> relatively small populations of patients.
>
> To my knowledge, they have not been widely applied to products that
> have widespread use in the population in that instance where they are
> being used as a form of gate-keeping in terms of access to the
> program.
>
> They do offer the opportunity to collect information on a population.
> It is important, however, that these registry programs be really
> highly focused on issues of product safety rather than research. There
> are some human subject concerns in setting up such programs.
>
> DR. KATZ: Final question to Dr. Aronson.
>
> DR. ARONSON: You mentioned education and outreach in the same breath,
> and I guess I would like to differentiate them at least in my own mind
> as one being, I suppose, verification of knowledge, not only teaching,
> but also to verify that the idea was received, whereas, the other is
> promotion of an idea over concept without necessarily verifying that
> it was received.
>
> In that light, you have noted that there isn\'t any data to suggest
> that it makes a difference, although we all have our sense that it
> does.
>
> Are you saying that because you are not differentiating those two
> processes of education and outreach, or because you have and it
> doesn\'t matter no matter how you do it?
>
> DR. TRONTELL: I may not be making the same distinction in those two
> terms that do. The distinction of some form of education that actually
> requires some certification that a level of knowledge has been
> attained. In fact, we might categorize in the guiding systems, which
> is that a certain level of competency needs to be demonstrated to an
> external body prior to the ability to prescribe, in contrast to the
> others which are more passive and dependent on an individual reading
> and absorbing and applying that information.
>
> DR. KATZ: Thank you, Dr. Trontell.
>
> I realize we are getting to the part of the afternoon where
> everyone\'s stamina and energy is probably at its nadir for the day.
> What we will do is we will take a eight-minute break. We will resume
> with the final presentation from Dr. Winchell and then we will have a
> focused and productive discussion until 5:00.
>
> \[Break.\]
>
> DR. KATZ: It is my pleasure to introduce Dr. Celia Winchell who is
> Acting Deputy Director of the Division of Anesthetical, Critical Care
> and Addiction Drug Products, our sponsor, who will be speaking about
> current opioid risk-management plans.
>
> **Current Opioid Risk Management Plan**
>
> DR. WINCHELL: To kick off this afternoon\'s discussion, what is left
> of it, and tomorrow\'s discussion, I am going to be describing
> elements of existing risk-management programs for opioid drugs.
>
> \[Slide.\]
>
> Before I begin, I will run through the products that I will be
> mentioning in this presentation to familiarize you with them and their
> similarities and differences.
>
> I am including OxyContin, Avenza and Palladone which are within the
> group of modified-release opiates that we are primarily concerned with
> today and tomorrow. Others, including Actiq, Suboxone, Subutex and
> Tramadol are not really in the same category but the issues of concern
> were similar and the programs have many similar features.
>
> OxyContin, as you know, is a modified-release formulation of
> oxycodone. Avenza is a once-a-day oral morphine. Palladone is a
> modified-release hydromorphone. Actiq is a high-dose fentanyl product
> formulated into an oral transmucosal dosage form resembling a
> lollypop.
>
> For Actiq, the primary concern was the high potency of the product and
> the potential for accidental overdose, either in patients, themselves,
> due to improper patient selection or in household contacts of the
> patients, especially children who might be attracted to the product
> because of its formulation.
>
> It is sweet, raspberry flavored, could be mistaken for candy. Because
> of this unique concern related to the formulation, specific aspects of
> the risk-management program for Actiq were included as conditions of
> approval under Subpart H.
>
> Tramadol is an analgesic whose abuse potential was somewhat uncertain
> at the time of its approval. So the important issue at the time that
> this particular program was put into place was early detection of
> abuse and misuse.
>
> Finally, Suboxone and Subutex are two bupranorphine formulations for
> agonist treatment of opioid dependence. All of the issues brought up
> by the opioid analgesics were relevant to these products as well but
> there is naturally less emphasis on encouraging doctors and
> pharmacists to avoid providing the product to patients with drug abuse
> problems.
>
> Just to keep your interest, because I know everybody is tired, we can
> make a little game of finding the times that I say Suboxone-Subutex
> and the times I say Subutex-Suboxone because I know I am inconsistent.
> Also, you can find the times I left the Capital C out of OxyContin.
>
> \[Slide.\]
>
> Three themes are prominent in these programs. First, the prevention of
> accidental overdose or unintended exposure; this refers to possible
> overdoses in patients, themselves, who lack opioid tolerance and to
> the possibility of household contacts including children being harmed
> by accidental exposure to the products.
>
> Second is the encouragement of proper patient selection. This
> subsumes, basically, two things. On the one hand, providers are urged
> to ensure the drug isn\'t given to someone who will be harmed by it.
>
> So, in the case of some high-potency or high-dose products, this would
> include opioid-naive patients but it also includes patients who don\'t
> actually need opiate treatment and would, therefore, have no
> justification for being exposed to the risks of physical dependence,
> withdrawal and overdose
>
> Then the other aspect of proper patient selection refers to making an
> effort to ensure that the recipient of a prescription is, indeed, a
> legitimate patient, not a fraudulent patient with criminal intent who
> is obtaining the prescription from misuse, abuse or sale. Thirdly, the
> programs address the general topic of preventing and detecting misuse
> and abuse.
>
> The programs generally employ several different features that have
> been listed among the possible components of risk management plans,
> education and outreach to patients, physicians and pharmacists have
> been incorporated in various ways. Some programs have also
> incorporated mechanisms to ensure safe and appropriate use along the
> lines of what was termed guiding systems by Dr. Trontell\'s
> presentation.
>
> Some features intentionally restricted distribution to pharmacies
> early in launch and all included some form of targeted surveillance in
> addition to the usual passive collection of adverse event reports with
> the stipulation that some sort of prevention measures would be
> undertaken in the case of concerning trends.
>
> I will run through some of these components were operationalized
> across risk management programs, but let me emphasize that the
> examples I am giving will not be exhaustive, just representative.
>
> \[Slide.\]
>
> Education has been an important component of virtually all of these
> programs. Patient package inserts in consumer-friendly language have
> been made available to alert patients to important information about
> use of their medications. Each one also emphasizes the risk of
> overdose and the need to store the product securely away from
> household contacts who could be harmed by exposure to the products.
>
> A public service campaign about the risks of prescription drug abuse
> has been a component of one program. Training materials and courses
> for physicians and pharmacists have also been developed and some
> companies have established call centers or web sites to provide
> information about their products.
>
> Some programs have been targeted to particular medical specialties,
> but a challenge for these education and training programs for these
> modified-release opioids is the broad range of prescribers as was
> mentioned to use in Dr. Rigoni\'s presentation of prescription usage
> data.
>
> I will go through in a little more detail what some of these
> educational programs include.
>
> \[Slide.\]
>
> The Subutex-Suboxone risk management program includes a brochure for
> physicians that is separate from the package insert. This brochure is
> Answers to Frequently Asked Questions. It is about the nuts and bolts
> of using the product. Because special qualifications and a special
> notification process involving HHS and DEA are needed before using
> Subutex and Suboxone to treat opiate dependence, this brochure walks
> the doctors through that process.
>
> It also gives tips on storage and recordkeeping, so doctors will feel
> comfortable keeping a supply on hand in order to provide supervised
> dosing, and it gives some tips on preventing diversion, just simple
> things like writing prescriptions in a way that makes them less likely
> to be altered, keeping your prescription pads secure, and so on.
>
> There are many opportunities for in-depth physician education on these
> products, some provided by the sponsor, but many provided by the
> Substance Abuse and Mental Health Service Administration.
>
> These are conveyed through web sites and through professional and
> through professional organizations and fulfill the legal requirements
> for training that is part of the notification process.
>
> \[Slide.\]
>
> For Actiq, the physician education component is aimed at specialists
> in oncology and pain. In includes a CD-ROM that discusses child
> safety, proper patient selection, prevention of diversion and abuse,
> and proper handling of the product, emphasizing safe storage and
> disposal.
>
> Company made available a speakers\' bureau, they trained specialized
> detail reps to educate the healthcare providers about the product, and
> in addition, put together a professional information kit and made that
> available to physicians.
>
> \[Slide.\]
>
> The program for OxyContin has included physician education materials
> that address the use of opiates in medical practice. An anti-diversion
> brochure gives specific information about how individuals obtain
> prescription drug from unwitting physicians through theft or
> alteration of prescriptions or through the fabrication of clinical
> scenarios that persuade the physician to write a prescription for the
> desired product.
>
> These brochures alert doctors to these techniques in order to help
> them guard against them. In addition, materials on pain diagnosis and
> management were developed, were funded and made available, and, in
> addition, a CD-ROM-based training program and series of lectures
> covering both topics was disseminated.
>
> Several program include education directed specifically at
> pharmacists. I will run through some examples. Prior to the approval
> of Suboxone and Subutex, pharmacists actually had no role in the
> agonist treatment of opiate addiction because it was illegal under the
> Narcotic Addict Treatment Act to prescribe the treatment. It had to be
> dispensed at specialized clinics.
>
> So, therefore, the entire concept of pharmacist seeing patients coming
> in to fill prescriptions for this type of treatment was novel, so a
> pharmacist brochure was developed which, in addition to the usual
> pharmacologic information about the product itself, explained the
> requirements for physicians under the Drug Abuse Treatment Act,
> described the new role of pharmacists in addiction treatment, gave
> some helpful information about confidentiality and other things that
> we thought would be useful to pharmacists.
>
> The seminars at pharmacy professional meetings are also being
> sponsored to educate pharmacists about various issues in addiction
> treatment and specifically about the products.
>
> \[Slide.\]
>
> The Actiq program emphasized enlisting the assistance of pharmacists
> as gatekeepers. Through Dear Pharmacist Letters and ads, pharmacists
> were prompted to check that the product was not prescribed off-label,
> and they were to play a role in ensuring the product did not go to
> opiate-naive patients.
>
> In addition, the pharmacists were enlisted in giving child safety
> messages and giving the materials that are intended to prevent
> accidental exposure.
>
> \[Slide.\]
>
> A number of programs have employed tools which fall broadly in the
> category of guiding systems. These have been described as mechanisms
> or processes that help well-intentioned people to do the right thing.
>
> For example, the OxyContin program featured distribution of
> tamper-resistant prescription pads to physicians that would help them
> ensure their prescriptions would be less likely to be altered, and
> because keeping the product safely away from children in the home is a
> key message of the Actiq program, the patients are provided with a
> Welcome Kit that gives them the tools to do just that. The kit
> contains cabinet locks, a locked bag for storing drug supply,
> child-resistant disposal container, and, in addition, the Actiq
> program incorporated prompts in the pharmacy software programs that
> are used in major chains. It was to encourage pharmacists to verify
> the patient was opioid-tolerant and to inquire whether there were
> children present in the home to make sure they got the appropriate
> child safety messages.
>
> \[Slide.\]
>
> Although not the type of closed restricted access system that Dr.
> Trontell described associated with clozapine or thalidomide, some
> element of restriction of access is included in several of these
> programs.
>
> Most obvious is control under the CSA. That is a form of restricted
> access. Not everyone can write a prescription for a controlled
> product, only physicians with a DEA license can write prescriptions
> for controlled products.
>
> In addition, Schedule II control, which prevents phone-in
> prescriptions, disallows refills, and tends to prompt pharmacist
> scrutiny is in place for most of these products.
>
> An additional restriction is in place for bupranorphine. Legislation,
> the Drug Abuse Treatment Act, exists that permits agonist treatment of
> opiate addiction outside the clinic setting using specific
> medications. At present, it applies only to bupranorphine.
>
> Under this law, the physicians must meet certain criteria. It must go
> through a notification process to obtain a special identification
> number from DEA, and this identification number identifies the
> physician is qualified to use the product.
>
> Some programs also include mechanisms to limit the distribution of
> products through retail pharmacies, and they have monitoring to make
> sure the sales match up with the geographic location of legitimate
> prescribers and patients.
>
> \[Slide.\]
>
> One very prominent feature in these programs is the inclusion of
> surveillance above and beyond the usual approaches to
> pharmacovigilance that are employed by pharmaceutical companies.
>
> Each program has specific mechanisms or studies to detect early
> signals that problems are occurring. The Actiq program featured a
> series of checks and balances. Pharmacists are surveyed to ensure that
> the drug is being prescribed by physicians on label. Physicians are
> surveyed to ensure that the pharmaceutical detail reps are delivering
> the appropriate information, and patients are surveyed to ensure that
> pharmacists are delivering safety messages.
>
> \[Slide.\]
>
> Almost every program incorporates monitoring of various publicly
> available databases, both commercial databases and
> government-sponsored ones. Sponsors monitor prescription databases,
> such as IMS Health, to get the type of drug usage information we saw
> presented this morning, and in addition, some may include monitoring
> of the ARCOS database, the DEA-administered program.
>
> Risk management programs also include monitoring of databases, such as
> DAWN and the Toxic Exposure Surveillance System, to get information
> about overdoses and other adverse experiences and to keep an eye on
> how the drug is being discussed in the media and by the general
> public. Several sponsors have a formal approach to media surveillance,
> and also monitor internet discussion sites where information about the
> abuse of their products might be a topic.
>
> \[Slide.\]
>
> Where street use of the product is a concern, programs have
> incorporated ways to detect these trends through specific contact with
> individuals who are in a position to be aware of this use.
>
> Important informants in these programs include entrants into drug
> treatment. Some programs have tapped into a government-funded system
> known as DENS, the Drug Evaluation Network System. This program
> collects information about recent drug use from entrants into
> participating treatment programs using a computerized intake
> interview.
>
> The interview uses the Addiction Severity Index and therefore gives
> information about the characteristics of patients who report using a
> particular drug, such as their previous drug use treatment history.
>
> The sample currently includes 115 service delivery units across 79
> sites. The initial sample, much smaller, was largely urban, but rural
> and suburban areas were added in a recent expansion.
>
> For Suboxone and Subutex, an independent system of interviews with
> entrants into treatment was established, in which a cohort of 60
> programs in both urban and rural areas, treating both adults and
> adolescents, are to administer a product familiarity interview to
> their treatment entrants.
>
> This interview asks not only what drugs the specific patient has used,
> but asks what drugs he or she has heard about people using on the
> street.
>
> Other program features intended to tap into this question include
> surveys of law enforcement officials, quarterly surveys of individuals
> involved in drug abuse treatment and research, who have been termed
> \"key\" informants, surveys of physicians who have identified
> themselves as providing bupranorphine treatment, and semi-structured
> interviews with people involved in the drug-abusing street culture by
> trained ethnographers.
>
> \[Slide.\]
>
> To a greater or lesser extent, the various programs have identified
> interventions that could be taken if problems were detected through
> this targeted surveillance. In many cases where the problem might be
> tracked to improper patient selection or off-label use, the
> intervention involved retraining pharmaceutical reps and auditing
> promotional practices basically to ensure that doctors were being
> given the right information.
>
> The Actiq program went so far as to call for the sponsor to send
> letters or have pharmaceutical reps go visit doctors who were
> identified as off-label prescribers. In addition, the OxyContin
> program has explicitly identified as one possible intervention, the
> involvement of law enforcement in the area where diversion is
> detected.
>
> \[Slide.\]
>
> In summary, drawing from the risk management programs developed for
> various opioid products, I have given some examples of education and
> outreach efforts to physicians, pharmacists, and patients.
>
> I have described some guiding systems that help people remember to do
> what needs to be done to use the product safely. I have described some
> way that supply and access to these drugs are constrained, and the
> various approaches taken to surveillance for abuse, misuse, and
> diversion.
>
> Today and tomorrow, we will be asking for your input on the pros and
> cons of different approaches to each of these components of risk
> management and your insights on how risk management programs for these
> products can be optimized.
>
> Thank you.
>
> DR. KATZ: We have time for a question or two to Dr. Winchell. Yes.
>
> DR. GARDNER: Dr. Winchell, thanks for that comprehensive list. Can you
> tell us whether any of these have been evaluated? Do we have any idea
> of the effectiveness of any of these methods?
>
> DR. WINCHELL: A lot of these programs are very new and have not been
> evaluated. We don\'t have much data collected on some of them. I am
> going to turn to my colleagues from the division to give you any other
> information that they have about these programs.
>
> DR. RAPPAPORT: Unfortunately, we don\'t have any information that we
> can give you today. There is very limited information on a couple of
> the programs, and it is somewhat tangential to the discussions today.
>
> The one bit of information that I think will be useful to you will be
> provided to you tomorrow by the folks from Purdue Pharma on the data
> that is available from the OxyContin plan.
>
> DR. DWORKIN: I have a related question. After the program is approved
> and initiated, who is doing the evaluation of two things, the data
> that are collected by the program, whatever the program is, and the
> integrity of the program itself, is it simply that this is being done
> by the pharmaceutical company in-house, or does the Agency somehow
> provide monitoring and oversight of the collected data and the
> program?
>
> DR. WINCHELL: All of these programs provide for periodic reporting to
> the Agency of the data collected, and we evaluate those in contacts
> with other sources of information that we have, like our AERS
> database, so we get what they get.
>
> DR. KATZ: Dr. Skipper.
>
> DR. SKIPPER: You didn\'t mention modifying the drugs, such as with
> Suboxone, adding naloxone as a risk management mechanism or program. I
> would like to know how that fits in as a category.
>
> DR. WINCHELL: You could see it that way. Again, that is a strategy
> that has not had evaluation although it has theoretical appeal. It has
> been done once before, again without much evaluation.
>
> DR. SKIPPER: It doesn\'t fit into any of these categories, right, very
> well. It would be product alteration to reduce risk.
>
> DR. WINCHELL: I am going to let Dr. Rappaport answer that.
>
> DR. RAPPAPORT: I think we have somewhat shied away from that because
> the efforts that have been made by a number of different sponsors with
> these types or products to make agonist/antagonist formulations have
> been thus far unsuccessful, troublesome, both in the area of
> manufacturing and in clinical efficacy, and also the work that is
> being done there in the studies that are being done to evaluate the
> efficacy and the quality of these products is not completed, so we
> really don\'t have any data to present, but it has so far been rather
> disappointing and we are not as hopeful as we were a couple of years
> ago that that was going to be an alternative way to deal with this
> problem.
>
> DR. KATZ: Dr. Maxwell.
>
> DR. MAXWELL: Let me go back and ask again, and I am not quite sure who
> to ask, but I do want to clarify very specifically. On the targeted
> surveillance slide, there was comment that one of the things was
> surveys of interest in some drug treatment and the DENS program.
>
> There was also mentioned the key informant network and the street
> ethnography network. I really would like to know, has FDA received any
> reports from either the Suboxone or the OxyContin manufacturers and
> distributors about any of these three different surveillance methods,
> have they come back to you and said we have gotten this many people
> from DENS?
>
> DR. WINCHELL: Bob?
>
> DR. HERTZ: I am not Bob, by the way.
>
> \[Laughter.\]
>
> DR. HERTZ: Yes, we have some information. Some of it is going to
> actually be presented tomorrow by the company, so we will hear about
> some of the information that has been collected so far for programs
> that are common to the product to be discussed tomorrow, as well as
> OxyContin. So, we will hear some of that from Purdue.
>
> What was the rest of that?
>
> DR. MAXWELL: Suboxone. Again, this was one of the ones that was
> mentioned. What data have you gotten back on that one?
>
> DR. RAPPAPORT: You may have more on this, but that is a very new
> program, so we really don\'t have anything back yet.
>
> DR. KATZ: Dr. Aronson, then the last question to Dr. Portenoy.
>
> DR. ARONSON: Mine is very quick. You mentioned in your discussions of
> methodology, the granting of a specialized DEA licensure or privilege.
> What is that mechanism or what would you propose it to be?
>
> DR. WINCHELL: Was this about the Drug Abuse Treatment Act, the special
> DEA identification number associated with bupranorphine treatment, is
> that the question? Okay.
>
> I am going to hope that my friends from DEA and CSAT will run up here
> and tackle me if I am very wrong, but the Drug Abuse Treatment Act
> requires that physicians notify the Department of their intent to use
> bupranorphine. They have to certify that they have the necessary
> qualifications and that they have the necessary facility to provide or
> refer patients for ancillary treatment, that they will restrict
> themselves to treating a limited number of patients at a time, and
> this notification goes through the Department of Health and Human
> Services in the person of CSAT, and to DEA, where if HHS finds the
> person is qualified, they ask DEA to issue an identification number.
>
> The identification number then can be used on prescriptions or in
> other venues to indicate that the physician has complied with the
> requirements for notification.
>
> DR. ARONSON: What is qualified? How do you define that?
>
> DR. WINCHELL: Qualified is defined by law\--Nick, do you want to
> answer this? This is the expert on this law from the Center for
> Substance Abuse Treatment, Nick Ruder.
>
> DR. RUDER: The qualifications are established in the statute. The
> physician must have a license to practice medicine, and it\'s a
> physician, it rules out nurse practitioners, physician assistants, and
> things like that.
>
> The physician must have a valid DEA registration and the physician
> must be qualified by training and experience, and training and
> experience in this case means either certification by three or five
> societies, medical societies, the American Society for Addiction
> Medicine, the Osteopathic Society, and the American Academy of
> Addiction Psychiatry, or it could be eight hours of training in
> addiction treatment.
>
> That is all specified in the statute, and the statute even goes on to
> say that eight hours of training can be by electronic means, so eight
> hours of training offered by an electronic web site also qualifies as
> training and experience under this law.
>
> So, physicians certifies he will treat 30 or fewer patients, they have
> the capacity to refer patients for other ancillary services, have a
> DEA registration, license to practice medicine, and the qualifications
> and training I talked about.
>
> DR. WINCHELL: To the extent that you might be getting some ideas about
> how this could be applied in the current situation, it is helpful to
> know that this law took probably five years to get passed.
>
> DR. KATZ: I am actually going to hold off on further questions for now
> unless anyone wants to sell one of their children for a question or
> something like that.
>
> Okay. Go ahead.
>
> DR. PORTENOY: I would actually like to sell three of my children.
>
> DR. KATZ: Oh, no, I already have four, that was a mistake, I take it
> back.
>
> \[Laughter.\]
>
> DR. PORTENOY: This is a very, very important question, so my thanks to
> the Chairman.
>
> From this broad framework of balance, has the Agency given any thought
> in the evaluation process to looking at the adverse effects of pain
> control on legitimate patients from any of these interventions? If
> not, why not?
>
> DR. WINCHELL: Bob.
>
> DR. RAPPAPORT: We have definitely given it thought. It is a topic we
> actually brought to you today to ask how to do that, what we should be
> looking for in those kinds of programs. It is clearly an issue we have
> been thinking about since you actually brought it up two years ago at
> the last meeting.
>
> DR. KATZ: I have a very ambitious agenda for the last 18 minutes or so
> of our session for today. So, hopefully, with the help of the
> Committee, we will be able to accomplish it, which is to answer
> Question No. 1 on the list of questions that we have.
>
> Dr. Rappaport, you wanted to intercede with a comment before we do
> that?
>
> DR. RAPPAPORT: I want to just give a little clarity to my earlier
> comment about the purpose of the meeting, the discussion that we are
> about to undertake, and that will probably continue into tomorrow, is
> a general topic discussion. It is not specific to Palladone. It is
> followed by a specific question related to Palladone tomorrow, what
> will probably be tomorrow afternoon by that time, and how we then
> apply that to other similar products and any recommendations that we
> glean from your discussion and comments, how we then apply that to
> other similar products is still under discussion.
>
> **Committee Discussion**
>
> DR. KATZ: The last 16 minutes of our agenda. I want to try to answer
> Question No. 1, so if everybody could go in their packets and look at
> Question No. 1, which is actually very short.
>
> I think the way that we can actually make some progress on this
> question in the next 15 minutes is for me to\--I will read it to you,
> but then I will break it up into what I think are more digestible
> chunks, that I think are relatively non-controversial at this stage,
> but yet very important to the process of our meeting.
>
> The question reads: Please discuss the role of the potent,
> modified-release opioids in the management of chronic pain.
>
> What I am going to do is break that up into four pieces. I will read
> you all those four pieces now and then I will re-read No. 1. I am
> going to start with No. 1 and see if we can work our way through No.
> 4, if that makes any sense to anybody.
>
> Here are the four pieces that I would like to break that question up
> into.
>
> Question No. 1 is are there certain types of patients for whom
> moderate-release opioids for the treatment of chronic pain are
> appropriate, or to put it the other way, are there certain types of
> patients for whom moderate-release opioids are not appropriate, and
> the dimensions of patient status that we could consider are there is
> certain types of pain intensities, moderate, severe\--you heard that
> discussion battered about earlier\--for whom these opioids should be
> contraindicated or for whom they are indicated, are there certain
> diagnoses for which we can say they are or are not indicated, et
> cetera.
>
> I will go through all of them and then I will go back to No. 1. The
> next piece is are there certain patients that are at higher risk for
> complications of opioid therapy that potentially could be identified
> upfront and perhaps be triaged into a different sort of treatment
> program or paradigm or clinic or specialist, et cetera.
>
> No. 3 is, is there an appropriate duration of treatment or is there a
> duration of treatment that we can say a priori is never appropriate.
>
> No. 4 is, is there an appropriate or inappropriate dose of opioids
> that we can identify.
>
> Those are the four pieces. I know that people didn\'t take them down,
> so I will go through them now, one by one.
>
> So, Question No. 1 or Subquestion No. 1 is: Is there any class of
> patients that we can identify a priori for whom long-term treatment
> with opioids is not appropriate?
>
> Let me actually prompt the group even further. Is there any level of
> pain intensity for whom we can say, at the outset, that opioids are
> not appropriate? People with moderate pain, people with severe pain,
> mild pain, certain diagnostic types?
>
> Dr. Portenoy.
>
> DR. PORTENOY: It is easiest to go to the populations for which there
> is a worldwide consensus about the appropriate use of opioids to
> answer the question, so the populations for which there is very little
> argument around the world is patients with cancer and advanced medical
> illness, patients with AIDS who have advanced medical illness, and
> acute pain patients.
>
> I think, as a general rule, in all those populations, what the
> guidelines around the world say is that anybody with moderate to
> severe pain should at least be considered a candidate for opioid
> therapy.
>
> So, the population that is not a candidate is the population of
> patients whose pain is generally mild, otherwise, they are all
> potentially candidates.
>
> DR. KATZ: Does anybody have anything to add to that or disagree or
> care to amplify? Yes, Dr. Skipper.
>
> DR. SKIPPER: I am wondering if rather than use the terms \"moderate\"
> or \"severe,\" it is better to look at function, you know, pain that
> inhibits, you know, active function, or is there any question about
> those terms? They are so relative.
>
> DR. PORTENOY: Could I answer that because I also didn\'t want to leave
> the impression that the guidelines or the consensus that has been
> applied for patients with advanced medical illness are being viewed as
> being simply transposable to chronic, nonmalignant pain. I didn\'t
> mean to say that.
>
> But I think from the perspective of chronic, nonmalignant pain, there
> is a consensus, at least in the community of pain specialists that is
> gradually evolving that patients with chronic, moderate to severe
> pain, which has impact on quality of life should at least be
> considered for opioid therapy, but one has to consider what
> conventional practice is, one has to consider whether other types of
> therapies exist that might have a better risk-benefit ratio, and one
> has to consider whether or not those patients have the capacity for
> responsible drug use.
>
> So, the considerations in the population without advanced medical
> illness become more complex and require greater assessment, but the
> bottom line is that as a broad population issue in terms of pain
> severity, it is moderate to severe from a verbal report perspective,
> and not requiring them to function poorly.
>
> DR. KATZ: What I am hearing from you, you are telling us that there is
> more or less a worldwide consensus that patients with terminal
> illnesses or life-threatening illnesses essentially regardless of pain
> severity are appropriate candidates for consideration of opioid
> therapy.
>
> I don\'t hear anybody disagreeing with that. Somebody can flag me down
> if they do.
>
> The next category, the much larger category, as we have learned, is
> those patients with chronic pain not related to terminal illness, and
> I am hearing from you that in patients with nonmalignant pain, whether
> it be moderate or severe in intensity, opioid treatment can be
> appropriate long term given the other considerations that you had
> mentioned.
>
> So, in other words, what I am trying to say is that even patients with
> moderate pain, nonmalignant in nature, should not be excluded from
> opioid therapy, but should be considered with the other provisos that
> you mentioned.
>
> DR. PORTENOY: Again, this is from my perspective. If one goes through
> an assessment of the patient and thinks about what conventional
> practice is, what the risk-benefit ratio of alternative treatments
> are, and whether or not the patient has the capacity for responsible
> drug use, they will end up being a subpopulation of patients whose
> verbal report is that they have moderate pain for which opioids appear
> to be the safest and most appropriate therapy, but there will be a
> large number of patients for whom opioids shouldn\'t be considered,
> because either conventional practice is very much against it or
> because the risk-benefit ratio falls on the side of trying alternative
> approaches first.
>
> DR. KATZ: Does anybody disagree with that in the sense that they feel
> that patients with pain who by verbal report is in the moderate range,
> should be categorically excluded from long-term opioid therapy? Is
> there anybody at this table that feels that way? Dr. Leiderman.
>
> DR. LEIDERMAN: Just a question, clarifying for Dr. Portenoy. When you
> say \"opioid therapy,\" now, are we talking about all opiates, or
> immediate-release, combination, short-acting, long-acting, and then
> sort of my corollary to that question is I think it is really
> important to distinguish because, of course, we are talking, we are
> differentiating, that is the point of the meeting, a particular class
> of high dose, high potency, extended-release opiates at this meeting.
>
> Then, I guess another corollary is do you conceive of an algorithm as
> being appropriate? In other words, should physicians in a best
> practice sense, either formally or informally, go through a reasonable
> algorithm that goes from non-opiates, NSAIDs, or whatever, up to
> immediate-release, combination, and then obviously depending upon
> response and failing at one of those levels, be moved on in a
> sequential way as the WHO guidelines suggest for cancer pain.
>
> DR. PORTENOY: I am glad you mentioned cancer pain at the end because
> my thinking is that it is always good to start with that population
> and then to think about how this moving target of what is appropriate
> opioid prescribing looks today and what has to happen to make it go
> forward in an appropriate way.
>
> In the cancer population, there has been an ongoing controversy for 10
> years about whether or not the latter is necessary, and there have
> been a couple of studies to show that patients with moderate pain do
> completely well with long-acting analgesics, with modified-release
> analgesics if the doses are adjusted appropriately, so they are
> started at very low doses.
>
> From the pharmacological perspective, there is nothing magical, as you
> know, about a modified release opioid. If the dose is adjusted
> appropriate to the level of the patient\'s prior opioid exposure and
> pain, the patient should do well with that, and so the latter was
> developed as a teaching tool, but shouldn\'t be viewed as dogma, as
> the only way you can treat a cancer patient.
>
> So, from that perspective, can you bring that paradigm into the
> nonmalignant population? I would say yes, you can. I think the first
> decision to make is whether or not a patient is a candidate for
> long-term opioid therapy, and if they are a candidate for long-term
> opioid therapy, then, the question is which drug to be started, at
> which dose, monitored in an appropriate way over time, so that the
> therapy remains safe and can have the best chance for effectiveness.
>
> If a patient has mild pain, I think everybody would agree that an
> opioid is not indicated or it would be perfectly reasonable to try a
> non-opioid first. If a patient has moderate pain, and they are still
> functioning well, that might be perfectly appropriate, as well.
>
> Even if a patient presents to the practice and they have severe pain,
> but they are coping well and functioning well, one might think to try
> an NSAID first or an alternative non-opioid adjuvant analgesic with
> other modalities first.
>
> I don\'t think we should stipulate that a specific therapy should be
> attached to a certain pain intensity, but if the entire clinical
> setting supports the use of opioid drugs, based on an assessment of
> the patient including a risk assessment, then, the selection of the
> drug follows, to me, the same guidelines as appropriate for cancer
> pain.
>
> In some cases, that would be to start with a short-acting and titrate,
> in some cases, it might be to start with a long-acting. Some of my
> best cases, parenthetically, have been elderly people that I have
> started on once-daily drugs at very low dose, because I can be sure
> adherence to therapy, I find it easy to monitor, and I can adjust the
> dose to make it safe.
>
> DR. KATZ: Dr. Bril.
>
> DR. BRIL: I guess I have a slightly different viewpoint for chronic,
> nonmalignant pain. First, pain severity. Someone with mild pain, I
> don\'t know that you need to go to an opiate at all.
>
> So, we are talking about moderate and severe, so if you have carcinoma
> or cancer or terminal HIV or something like that, then, I have no
> trouble going directly to an opioid. If it\'s a chronic, nonmalignant
> situation, I do have a lot of trouble because I haven\'t yet heard
> anything that will predict, for me, the patients will have trouble
> with the addiction or tolerance.
>
> In all the studies I have seen, the patients who were on opiates for
> nonmalignant pain have the complications or adverse effects that are
> typical of the class, so, therefore, they have the potential for
> tolerance even though I know in diabetic neuropathy, they say that
> they don\'t get that with Tramadol, I just don\'t know about that.
>
> So, I would think that for nonmalignant pain, what appears to be most
> reasonable for me, with moderate pain, is that you go through
> alternative therapeutic approaches, and that that will actually be
> what is advocated.
>
> I just have a real problem in going directly to slow-release or
> fast-acting or any kind of opiate that has all those potentials for
> the complications and addiction, and I haven\'t really heard anything
> today that can identify for me definitely the patients who will run
> into trouble with that.
>
> I mean I am really happy to learn more about it if I could, plus I
> haven\'t heard that this class of drugs is more effective really in a
> resounding way, say, as opposed to the tricyclic antidepressants for
> neuropathic pain or the anticonvulsants. I mean I haven\'t heard that
> one is clearly superior, and they will all have side effects. I mean
> everything we use will have side effects, so I would think you might
> start with the least and then build up. That is basically how I would
> think.
>
> DR. KATZ: Let me try to summarize what you just said, which seems to
> me that you feel that opioids should not be used until other therapies
> which have demonstrated safety and efficacy have been tried first and
> have not been satisfactory. Is that your point?
>
> DR. BRIL: Pretty well, yes, because I have found, I guess for these
> patients, they do need chronic therapy, so I think the potential for
> abuse then increases, I would think, but, you know, I am not for sure,
> but they do need chronic therapy.
>
> I found very few of my patients that can be treated for a few weeks or
> a few months and then stop treatment. They are on the treatment for
> years.
>
> DR. KATZ: Certainly, if that recommendation echoes throughout many of
> the guidelines for use of long-term opioids that are available, I
> don\'t think you would disagree with that, Russ, do you?
>
> DR. PORTENOY: No, I think we are in screaming agreement for the most
> case, but I think in the absence of good\--there aren\'t good data to
> show that opioids work in all different kinds of pain syndromes, as
> you know, and there is a little comparative data as the study that Nat
> talked about before that compared a tricyclic with morphine in
> diabetic neuropathy, but we are in a situation where we don\'t have
> enough efficacy or safety data for long enough periods of time, in
> appropriately selected subpopulations to be able to know in a very
> certain way, so it is in the realm of clinical judgment.
>
> If you have a patient\--I am just thinking in terms of case
> examples\--but if you have a patient at the age of 60, who has an
> evolving painful diabetic polyneuropathy, had no prior history of
> substance abuse, has no family history of substance abuse, but has
> some significant risk factors to anticonvulsant and antidepressant
> therapy, and hasn\'t responded to NSAIDs over the counter, and that
> patient is no longer able to function well because the pain is
> becoming chronic and debilitating and sleep is interfered with, and
> the patient is developing a mood disorder, and in your mind, you go
> through the risk-benefit ratio of thinking shall I start this patient
> on an opioid, or put this patient at some additional significant risk
> by trying a tricyclic or an anticonvulsant, I would think that the
> data at this point in time would support that route.
>
> Again, if you are saying, well, where is the study to show that this
> 60-year-old diabetic with painful polyneuropathy, predisposed to side
> effects from anticonvulsants and antidepressants, with no prior
> history of substance abuse and a negative family history, is going to
> do well six years later, I don\'t have that data.
>
> I would say, well, where is the data that they are going to do well
> with the tricyclic, you don\'t have those data either. So, I think
> that is the realm, that is the situation we are in.
>
> DR. KATZ: So, with apologies to people who have questions and are
> waiting, I am not going to let this point go until it is done since
> it\'s two minutes of 5:00. I don\'t hear anybody saying that patients
> with pain of moderate intensity should categorically be excluded from
> opioid therapy. Everyone is saying that there may be other
> considerations involved in choosing the therapy, which is the same for
> any medical treatment for any condition.
>
> This is nothing new for physicians that there might be treatment
> considerations other than one simplistic one. But I don\'t hear
> anybody saying that patients whose pain is of an intensity that is
> moderate should categorically be excluded from opioid therapy.
>
> Am I missing something here, Dr. Skipper?
>
> DR. SKIPPER: I want to say one thing. It seems like to me that I still
> think that function needs to be the key element. Even if somebody has
> mild pain, and they are not able to function, then, that might be a
> candidate, because I think the problem with these mild, moderate,
> severe is if somebody wants the drugs, and you say, well, you have to
> have moderate pain to get it, well, oh, yeah, I have moderate pain.
> But if we analyze it from the function point of view, which is what we
> look at to decide if it\'s working, are they improving their function.
> If there is no decrease in function to begin with, how do we know?
>
> DR. KATZ: I understand your point. It doesn\'t sound like you are
> disagreeing with me.
>
> DR. SKIPPER: I am disagreeing to use that as a measure, to say that
> patients with moderate to severe pain would be candidates.
>
> DR. KATZ: You are saying that you would be more inclusive than that
> and allow patients with even lesser degrees of pain intensity, but
> functional impairment also\--
>
> DR. SKIPPER: Look at it from a whole different perspective, and not
> use those degrees at all.
>
> DR. KATZ: Fine, that\'s great.
>
> It\'s 5 o\'clock. I am going to defer to the folks from FDA to see if
> they have any concluding comments from our session today.
>
> Sorry, one announcement that I have been asked to make about 20 times,
> and I have forgotten every time.
>
> It is not appropriate for people on the Advisory Committee to speak
> about Advisory Committee matters between now and 8 o\'clock in the
> morning when you are sitting around the table, and I will see you
> then.
>
> \[Whereupon, at 5:00 p.m., the proceedings were recessed, to resume on
> Wednesday, September 10, 2003, at 8:00 a.m.\]
>
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