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
PAGE
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 (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 R O C E E D
I N G S
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