ATDEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
ANESTHETIC AND LIFE SUPPORT DRUGS
ADVISORY COMMITTEE
Wednesday, September 10, 2003
8:00 a.m.
Holiday Inn Bethesda
Bethesda, Maryland
PARTICIPANTS
Nathaniel P. Katz, M.D., Chair
Johanna Clifford M.S., RN, BSN, Executive Secretary
MEMBERS:
Solomon Aronson, M.D.
Madelyn Kahana, M.D.
Steven L. Shafer, M.D.
Mary Beth Bobek, Pharm.D., Consumer Representative
Vera Bril, M.D.
Bhupinder Saini, M.D.
Carol Rose, M.D.
VOTING CONSULTANTS:
Louis E. Baxter, Sr., M.D., Drug Abuse Subcommittee
Domenic Ciraulo, M.D., Drug Abuse Subcommittee
Stephanie Crawford, Ph.D., M.S., Drug Safety and Risk Management
Advisory Committee
John Cush, M.D., Arthritis Advisory Committee
Robert Dworkin, Ph.D.
Jacqueline Gardner, Ph.D.,
M.P.H., Drug Safety and Risk Management Advisory Committee
Jane Maxwell, Ph.D., Drug Abuse Subcommittee
Gregory Skipper, M.D., F.A.S.M., Drug Abuse Subcommittee
Brian Strom, M.D., M.P.H., Drug Safety and Risk Management
Advisory Committee
David J. Wlody, M.D.
James Gillett, Ph.D., Voting Patient Representative:
Charles McLeskey, M.D., Industry Representative
NON-VOTING PARTICIPANTS:
Mary Jeanne Kreek, M.D.
Laura Nagel
Terrance Woodworth, M.D.
Judy Ball, Ph.D.,, M.P.H.
Joe Gfroerer
Arthur G. Lipman, Pharm.D.
Elizabeth Willis, Ed.D.
Deborah Trunzo
FDA STAFF:
Robert J. Meyer, M.D.
John Jenkins, M.D.
Bob Rappaport, M.D.
Sharon Hertz, M.D.
Deborah B. Leiderman, M.D., M.A.
Anne Trontell, M.D., M.P.H.
C O N T E N T S
Call to Order and Opening Remarks,
Nathaniel Katz,
M.D. 4
Conflict of Interest
Johanna Clifford,
M.S., RN, BSN 5
Committee Discussion 7
Sponsor Presentation:
Palladone Capsules for the Management of Persistent
Moderate to Severe Pain in
Opioid-Tolerant
Patients
Palladone Risk Management Program,
J. David Haddox,
D.D.S., M.D. 37
RADARS Surveillance System,
Sidney H. Schnoll,
M.D., Ph.D. 65
Prescription Drug Abuse, Herbert D. Kleber, M.D. 80
Questions from the Committee 88
Abuse Liability of Hydromorphone Extended-Release
Capsules, Silvia
Calderon, Ph.D. 125
Long-Acting Opioids: Challenges in Pharmacotherapy,
Mary Jeanne Kreek,
M.D. 143
FDA Presentation, Sharon Hertz, M.D. 179
Open Public Hearing:
Tom Stinson, M.D. 190
Art Van Zee, M.D. 192
Committee Discussion 201
P R O C E E D
I N G S
Call to Order and Opening Remarks
DR.
KATZ: Good morning. Once again, this is a meeting of the
Anesthetic and Life-Support Drugs Advisory Committee. My name is Nathaniel Katz.
I
wanted to make brief opening comments.
First of all, in terms of committee discussion and in terms of speaker
presentations, the ground rules for today will be the same as yesterday. If anybody around the table feels that they
want to direct any questions to anybody just raise your hand and we will
recognize you, and those would go through me.
Speakers will get a yellow light two minutes before the end of your
presentation and then a red light at the very end of your presentation.
There
will be some periods of time for discussion this morning. We are going to follow the same schedule as
everyone has received and as is out there on the table. There have been no changes to this point in
the schedule so we will start out with about a half hour or so to continue some
discussion from yesterday, then we will have presentations from our sponsor at
8:45 and the schedule will continue like that.
Today
is nominally a day to discuss the Palladone risk management program, however,
there are still general issues from yesterday that need to be discussed so I
will try to be clear during the discussion period, and I think the questions
are clear enough themselves, as to whether we are talking about general issues
on risk management programs or the Palladone program in particular. I have no other general comments. Bob Rappaport or any of the folks from FDA,
anything to add? If not, Johanna
Clifford will read the conflict of interest statement.
Conflict of Interest Statement
MS.
CLIFFORD: Thank you. The following announcement addresses conflict
of interest issues with respect to this meeting and is made part of the record
to preclude even the appearance of impropriety at this meeting.
The
conflict of interest statutes prohibit special government employees from
participating in matters that could affect their own or their employers'
financial interests. All participants
have been screened for conflict of interest in the product, competing products
and firms that could be affected by today's discussions.
In
accordance with 18 U.S. 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 include
Dr. Nathaniel Katz for consulting on an unrelated matter for the sponsor. He earns less than $10,001 per year. Dr. Robert Dworkin for consulting on
unrelated issues for three competitors.
He earns less than $10,001 a year from each firm. Dr. Steven Shafer for consulting for a
competitor. He earns less than $10,001
per year.
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 disclose 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 a shareholder.
In
the event the discussions involve any other products or firms not already on
the agenda for which an FDA participants 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 other participants, we 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.
Thank you.
Committee Discussion
DR.
KATZ: Thank you. Now we have about 40 minutes of time to
continue our discussion from yesterday.
If everybody around the table could return to their list of questions,
we will be continuing our discussion of question one which we were able to
begin very briefly towards the end of the day yesterday.
I
will read the question. Please discuss
the role of the potent modified-release opioids in the management of chronic
pain. We can just begin a general
discussion or continue a general discussion of that issue. Does anybody from the FDA side want to add
any clarifying comments to that question, or are you satisfied with beginning a
general discussion?
DR.
RAPPAPORT: Why don't we just begin with
a general discussion and if we feel the need to jump in, we will?
DR.
KATZ: We are open for comments. Yes, please, Dr. Rose?
DR.
ROSE: Yesterday you had asked several
questions about certain types of patients, certain patients at high risk for
adverse events, etc. and I wanted to put my two cents in on that.
I
felt that when you talk about types of patients we should also talk about the
physician doing the prescribing who needs to identify and document, if
necessary of patients who in the past, when they have cared for them, have been
unreliable and non-compliant. I think
that is the issue. Cases that I have
seen can kind of tell you in advance that these patients are going to have
problems with the type of drug that we are talking about today. So, I think it is very important for the
physician to actually evaluate the patient for their reliability. That was one issue that I wanted to make a
comment on.
Then
the other, when you are going to say about the duration of treatment--you are
going to be getting to that, I know--in the past there have been issues of
putting a time limit on certain types of care that we give to patients who are
considered to be terminally ill. There
is, for example, the issue that hospice is only for patients who you expect not
to live more than six months but, as was mentioned yesterday, many times if you
appropriately treat a terminally ill patient you can actually extend their life
and make their life more comfortable for whatever time they have left. So, I do think it might be inappropriate to
put a time limit or to say if you don't expect the patient to live more than a
certain period of time that this patient is a candidate for this drug and not
otherwise. So, I don't think that we
should put a time limit for terminally ill patients.
DR.
KATZ: Thank you. So, if I take your two points, you are
suggesting that, number one, in assessing the appropriateness of long-term
therapy one factor is assessing the likelihood of patient compliance with that
therapy.
DR.
ROSE: Correct.
DR.
KATZ: One element in that assessment is
history of compliance or non-compliance.
DR.
ROSE: Thank you.
DR.
KATZ: Then, the second point that you
are suggesting is that in the course of appropriate medical practice artificial
limitations on the duration of therapy are not part of normal medical practice
with opioids.
DR.
ROSE: That is correct.
DR.
KATZ: Other comments? Yes, Dr. Baxter?
DR.
BAXTER: Thank you very much. I am glad to see that on my first attempt
today I am in, not that I am still thinking about yesterday--
DR.
KATZ: God forbid!
[Laughter]
DR.
BAXTER: But I think that it is important
from an addiction standpoint that part of the appropriateness that should be
considered by physicians if in fact, number one, that there is a history of
addiction or use disorder and, number two, what is the current status of that
medical problem. It is my belief, and
the belief of many addiction specialists, that people who have histories of
addiction are not automatically excluded from use and benefit of opiate
medication, but it is very important to be able to ascertain that person's
recovery status.
DR.
KATZ: That is very helpful. So, again, you are suggesting that an
addiction history should be a standard element and in good practice is a
standard element of assessing a patient for the appropriateness of opioid
therapy. I wonder if you could expand on
that and maybe give us a little bit more information on what physicians do to
get an addiction history and the accuracy of those office-based methods in
obtaining an adequate addiction history.
DR.
BAXTER: The first thing is that the
questions have to be asked.
Unfortunately, I know that many times an addiction history is not
taken. So, one would minimally need to
ask if, in fact, a person has ever had any problems with drugs and/or
alcohol. If the answer is yes, well,
then further information needs to be gathered in terms of what substance was
the drug of choice; what measures in terms of treatment were employed; and what
the person's current recovery status is.
DR.
KATZ: What if the answer is no?
DR.
BAXTER: Well, then you have to figure
out how far you really want to go with that line of questioning. As an addiction specialist, of course, you
know that I would go much further but I think that in terms of primary care or
general practitioners who, we all know, prescribe a lot of these medications we
have to at least get them to start asking questions.
DR.
KATZ: Thank you. Dr. Dworkin?
DR.
DWORKIN: I have a question about the
question. The question seems to emphasize
the word "potent" and I don't think we have discussed that. Given a range of potency in the available
modified-release opioids is the potency, meaning the milligrams needed for an
equianalgesic dose, relevant in any way at all or not to clinical practice of
these modified-release opioids. So, I
guess my question is about have we really discussed potency variability among
these drugs? And, I don't think we have,
and should.
DR.
KATZ: So, are you asking the question
about whether the word "potent" changes the answer here?
DR.
DWORKIN: Yes, whether the potency of the
drug change has any impact on the answer.
DR.
KATZ: Or, are we just really discussing
about opioid therapy in general? Well,
that is a question and that is open for commentary. Is the standard of practice different for
opioids depending on their potency? Dr.
Saini and then Dr. Shafer?
DR.
SAINI: I think the WHO letter was made
on an arbitrary basis. There is really
no difference between a weak opiate and a strong opiate. You can give enough of a weak opiate and get
the same effect as compared to giving a smaller amount of a stronger
opiate. So, the main question is should
the opiates be used in pain. And, the
answer is, yes, if appropriately used they are the gold standard for moderate
to severe pain while NSAIDs should be used to control mild to moderate pain.
Having
said that, the risk of addiction should be assessed and at the same time the
adverse effects of narcotics should be assessed also as the therapy is going
on. While you are assessing these risks,
when you see these drug addicts nobody will divulge a history that they have
been in a drug rehab program. It is
usually later on that you find that these people have been in a drug rehab
program and you have problems. So,
assessing the history and if they are prone to becoming an addict is
important. Family history of drug
dependency, history of anxiety, depression, psychiatric disorder and previous
history of drug abuse makes them more prone to become a drug addict.
DR.
KATZ: Thank you. Dr. Saini, your answer to Dr. Dworkin is
no. You are saying that the word
"potent" could just as easily be taken out of this question and that
the standards of care and medical practice are the same for all opiates,
regardless of their potency or their release.
Am I understanding you correctly?
DR.
SAINI: That is correct.
DR.
KATZ: Dr. Shafer?
DR.
SHAFER: Dr. Dworkin's question is a good
one. I think it relates to the fact that
there are two definitions of potency that are used. To the lay public potent just means strong
and the strength has two components.
One, from a pharmacological perspective, is the concentration associated
with 30 percent maximum drug effect, which is the definition you are thinking
of, and that is absolutely irrelevant to the utility of the drug provided you
don't have to eat, you know, bricks of the stuff to get a drug effect. The other is the intrinsic efficacy, the
maximum effect the drug can produce, and all of the full mu agonists are
thought to pretty much go to the same maximum drug effect.
From
a pharmacologic perspective, I think what we are talking about is the full mu
agonists. If we want to be true to what
we are talking about here pharmacologically, we should perhaps talk about full
mu agonists and leave potency out of it.
I think potency is being used in a colloquial sense.
DR.
KATZ: So, your answer is also no to Dr.
Dworkin?
DR.
SHAFER: Yes.
DR.
DWORKIN: Can we ask the Division whether
potency is being used in a colloquial sense or in a pharmacologic sense in this
question?
DR.
KATZ: Yes, you can.
DR.
DWORKIN: Thank you.
DR.
RAPPAPORT: Thank you. This question refers to the use of the high
dosage, extended-release opiate products that are under discussion as a general
topic of the meeting.
DR.
KATZ: Maybe I can clarify that. Correct me if I am wrong, I think the
question was worded this way because that is what we are here to meet about and
it doesn't in any way mean to exclude other forms of opioids or get into the
issue of whether the practice standards might be different. Is that fair enough?
DR.
RAPPAPORT: Yes, although we would like
to have some focus on that particular group of drugs as it applies to this
meeting and also as it applies today to the ensuing discussion of Palladone.
DR.
KATZ: Yes, I think what we are hearing,
so far anyway, from the group is that the practicing patterns and standards are
the same regardless whether the opioid is more or less potent or modified
release or not modified release, if I am hearing the committee correctly. Does anybody think I am hearing wrong? Dr. Bril?
DR.
BRIL: My comment was more in the form of
a question to individuals running pain clinics; as I say, I run a more general
clinic. This applies to opiate therapy
and disclosure with the patient and exactly how the therapy is phrased to the
patient. I think it is important, in
chronic pain particularly, that the patient really be aware of the class of
drug they are taking. I mean, opiate may
mean a lot to us and so may pain killer but to the patient I think even being
very blunt and telling them they are taking a narcotic, with all the
implications that has, is something that may be considered because a lot of
patients won't really know what you mean if you just say opiate and if you say
pain killer, there are so many it is a non-specific term.
So,
for me, when I start a patient on this, because there is no definitive way that
I have of knowing who would be addicted, if I select the patient and think that
they are safe candidates for this kind of therapy I do warn them about the
class of drug I am using with them. I
just think that caution and full disclosure in a way that patients will truly
understand are necessary.
DR.
KATZ: So, you are suggesting that in
prescribing these medications to patients, just calling them pain killers
without being more specific about their class and their potential risk is not
sufficient.
DR.
BRIL: True. I mean, a nonsteroidal is a pain killer, or
aspirin is a pain killer if we use it in certain ways, which are quite
different from opiates. And, using the
word opiate isn't necessarily enough either, although you might think it is.
DR.
LEIDERMAN: First a comment and then a
question. I think that it is important
when we talk about pharmacologic potency to think about the multitude of
effects that drugs have, and equianalgesia does not necessarily equate to equal
effects in terms of psychic effect, euphorigenesis, reinforcing effects. We will come back to that with some data to
be presented later this morning, but that is a part of the very complex concept
of potency and I think that that is part of what we mean.
The
question part, I would ask the pain doctors here, I mean, do you prescribe
Dilaudid in the same way that you prescribe a codeine 30 mg? I would suggest not and it doesn't have to do
just with the different dosage strengths available. So, that is sort of my comment.
My
question is about something touched upon yesterday that I would like to have a
little bit more input on. What does the
committee think is the role of physician-patient care contracts in the context
of chronic, non-malignant pain treatment with high dose opiates?
DR.
KATZ: Let's leave that question in the
air. I want to make sure that I am not
missing people who are on line for comments.
Dr. Gillett, you are next.
DR.
GILLETT: When you are a layman this
whole business of indication is a very difficult proposition. After you have questioned your patient and
discussed their addiction, what choices do you have? Do you withhold from a patient who has gotten
squamous cell carcinoma as a consequence of alcoholism? You are going to withhold a pain killer like
one of these medications during radiation therapy when they elect not to have
surgery because their physician had a TV show and testified in court about drug
addiction and alcohol and drug-driving cases?
In other words, a friend of ours down in Greenville, South Carolina is
faced with this and he receives OxyContin.
DR.
KATZ: It sounds like you are agreeing
with Dr. Baxter that one needs to do a risk assessment and that some patients
may be at higher risk for complications, but that doesn't necessarily equate
with withholding therapy. Maybe what we
will get to in some point of our discussion is, well, what does that equate
to? What does one do in that
situation? Let's see, Dr. Skipper, you
were next.
DR.
SKIPPER: Because we are here primarily,
in my view, to talk about the risk of these drugs and the primary risk that we
are concerned about is the spiking epidemic abuse and the recruitment of new
addicts who take these drugs, some of whom die from overdose, going back to the
end of the day yesterday when you asked about mild, moderate or severe and I
was looking toward possibly encouraging a change in that terminology, which I
have now decided maybe to give up on, I would subsequently like to see more of
a move toward restricting the use for severe pain, if we define severe pain as
significant impairment of function, because I think we need to decrease the
amount of these drugs on the market because that will decrease the epidemic of
abuse.
DR.
KATZ: Won't you expand then on how you
would propose implementing that sort of an approach?
DR.
SKIPPER: Well, I would suggest that the
package insert say that these drugs, these potent extended- release opioids be
used for severe pain, and then define severe pain as significant decrease in
function associated with pain.
DR.
KATZ: Of course, we have an ambiguity
because most practitioners/researchers use the term mild, moderate and severe
as a measure of pain intensity on some sort of scale, so you would introduce
the term but then redefine it in a way different from its customary use,
focusing more on impact. But I still
would, you know, be interested in hearing you expand more on this notion of
impact on function as being a marker of the importance of the disease to the
patient and the importance of treating it aggressively.
DR.
SKIPPER: Well, as I said yesterday, I
think the way we monitor whether these drugs are effective is by looking to see
if function improves. If function is not
impaired, then I am not sure they should be used. So, I would like to see movement towards some
kind of policy that function be assessed.
Because that was not received well, then I am thinking that to redefine
mild, moderate and severe so that that it be associated with significant
decrease in function may restrict to some degree the use of these, which would
decrease the problem of substance abuse.
DR.
KATZ: So, just to clarify what you are
saying, it sounds like--correct me if I am wrong--is that even somebody whose
pain intensity level was rated using the word moderate but, yet, that pain
still had an impact on that patient's ability to function they would be a candidate
for opiate therapy in your mind because they would be reclassified as severe
based on your impact definition.
DR.
SKIPPER: I guess that is correct.
DR.
KATZ: Thank you. Dr. Ciraulo, you were next.
DR.
CIRAULO: Yes, Dr. Leiderman had
addressed some of the issues that I wanted to raise but I wanted to go back to
the issue of potency. I think that what
we are really talking about is abuse, liability and concerns about that and I
think that, yes, it is correct that most of the drugs we are talking about are
full mu agonists. We also have to think
about the pharmacokinetics of these drugs.
If you look at abuse liability across substances of abuse, you know the
drugs that are more rapidly absorbed and reach higher peaks are subject to
greater abuse liability.
I
think there are differences among the opioids.
Certainly, in the days when I did physician management of addicted
physicians there were patterns. There
were certain drugs that were preferred, and I think they correspond with a lot
of the PK of the full mu agonists and I think we have to keep that in mind as
we look at the data.
I
just wanted to add that I certainly support the use of these drugs in recovered
substance abusers. I think you should do
an assessment. You will make mistakes. I want to emphasize that when mistakes are
made people should not be prosecuted for these mistakes; this is going to be
part of the practice, but denying substance abusers who are in stable recovery
adequate pain management is inappropriate.
DR.
KATZ: So, you are then joining those who
have said that while risk assessment, including a substance abuse history, is
important. That doesn't mean that the
patient should necessarily be excluded from opioid therapy as a result of that
assessment. So, what are the
implications then for the use of opioids in such patients? If we are taking their history and
identifying their risk level are there any implications for management?
DR.
CIRAULO: Yes, definitely. I think you have to step up
surveillance. I realize that this would
be a problem in some rural areas, and I don't work in a rural area so I don't
have specific suggestions for that, but in areas where there are specialists I
think with more frequent visits, good contact with pharmacy, single-source
prescribing, and a lot of the things that we can do to monitor we can build in
good surveillance programs so that even if a substance abuser does end up
having any problems initially, I think it is inappropriate to say, "okay,
you're out." I think there should
be an algorithm to step up the surveillance.
DR.
KATZ: So, you are saying that patients
who are identified as being at higher risk, even if they are prescribed opioid
therapy, need to be prescribed it in a different sort of program than somebody
without those red flags for risk.
DR.
CIRAULO: Exactly. What we have done in the past--and I am not
saying we want to do this in the future but in the past we have put such
patients in methadone clinics. I am not
sure I would do that now; I think there are better ways to do it.
DR.
KATZ: Thank you. Next was Dr. Strom.
DR.
STROM: A couple of related
comments. I am a general internist; I am
not a pain expert and I certainly have no problem with the clinical
recommendations I am hearing and referring my pain patients to colleagues. But as an epidemiologist, my role is to be a
curmudgeon, and part of my concern about what I am hearing is that I would ask
my fellow committee members to differentiate when what you are saying is based
on data versus when it is based on opinion.
It is not clear to me virtually any of this is based on data and I think
it is important we make that clear when we give this advice to FDA because FDA
is a science-based agency and needs to make its decisions according to that,
and that ranges from clinical recommendations to recommendations about risk
assessment to try to predict addiction and thinking we really have the ability
to do that to recommendations about even restricting use and that that would in
any way affect the amount of addiction in society. I am not sure we have heard the data to
underlie any of that.
DR.
KATZ: Thank you. I think that is a very important point and I
want to get back to it but first Dr. Jenkins.
DR.
JENKINS: I would like to offer the
committee some clarification on what the intent was of this question because I
think you are verging into a much more general discussion about the role of
opioids in treatment of pain. We were
really focused on what is the role of sustained- release or modified-release
opioids in the treatment of chronic pain.
There have been some, for example, who have argued that these products
are simply convenient dosage forms and, therefore, the abuse liability and the
abuse potential and the actual abuse we have seen negates the value of these
products to the patients. So, our focus
of this question was not to get into a general discussion of when should you
use opioids in the treatment of chronic pain.
It was more to ask you to talk to us about the role of sustained- or
modified-release opioids in the treatment of chronic pain. So, hopefully, that can help you focus your
discussion so that we can get back from you all that we are looking for.
DR.
KATZ: Thank you for that
clarification. Let's then look at the
discussion in a different way and open up the floor for comments on the
particular role of modified-release opioids in the opioid management of
patients with chronic pain.
Actually,
as long as we are pausing for a moment, Dr. Leiderman did put this question in
the air about the use of patient care agreements. So, in light of this refocused discussion,
does anybody have any comments on patient care agreements? Go ahead, Dr. Rose.
DR.
ROSE: I get to look at liability
insurance claims and sometimes I see anesthesiologists or other physicians who
have had problems where there are not contracts. I can see situations where had this physician
used a contract and insisted that the patient comply we wouldn't have the
problems. I am very much in favor of
physician and patient contracts.
DR.
KATZ: For medical-legal reasons, it
sounds like you are saying.
DR.
ROSE: Yes, for medical-legal reasons and
also I think it helps the physician to help the patient. I think that contracts are very, very
important.
I
would like to make a comment about this issue of the concept of sustained
release. The concept of sustained
release I think is great. If we were
talking about a drug for sustained-release management of hypertension I think
all of us around the table would think that is great because if you want
someone to take a pill four times a day to manage their hypertension, that is a
problem because it is just hard to do.
The issue here is sustained release for opioids, and then the reason why
we are looking at that in a more focused way is because of the problem of abuse
and inappropriate use of the drugs. So,
I think that really our focus needs to be on how can we handle that abuse
because underlying it all I think most of us would agree that sustained release
anything is a good idea because it helps in better patient care.
DR.
KATZ: Dr. Kahana?
DR.
KAHANA: I would like to reiterate from a
non-epidemiologist what Dr. Strom had said because I feel like I am in a very
awkward position of trying to come up with recommendations with remarkably
little real data. I guess the question I
would have is would we be better off trying to define the patients who are not
good candidates for these drugs rather than the ones who are, and to define a
subset of patients who might be better off referred to people who are
specialists, either by direct referral or by telecommunication. We certainly have the ability to encompass an
enormous geographic area with expertise, if not by direct patient contact at
least by telecommunication with someone who is an expert. Could we not provide a mapping system for
people who would have the ability to access the experts in this kind of drug
dispensing? Because the restriction of
this class of drugs to those who really have chronic and sustained pain,
malignant or non-malignant in its origin, I think would be a real serious error
based on at least the data we have seen, which would lead me to believe that 50
percent of perioperative patients are getting the sustained-release
preparations which, I must say, I am a little skeptical to believe. So, even the data I think we have seen is
questionable at best.
DR.
KATZ: Yes, Dr. Ciraulo?
DR.
CIRAULO: Since you have redirected that,
I would like to re-approach the issue of the addicted patient. I have two comments and questions. One is if we believe--and this is a
question--if we believe that these drugs, these long-term and immediate-release
drugs are different in their abuse liability, if we say the drugs we are
evaluating have higher abuse liability, would the pain people feel comfortable
saying that this would not be a first-line drug for pain management in someone
with a history of substance abuse? That
is part one.
The
second part is if you use these drugs, do the pain experts have an idea of what
the risk is of creating a new addict in the patients they treat?
DR.
KATZ: That was a complicated question
and comment but it sounded like the first part of it was sort of a question
about whether the modified strong-release opioids have a higher abuse liability
than the immediate-release opioids. Was
that the first part?
DR.
CIRAULO: Yes, the extended release, for
example, can be chewed and has a very high abuse liability. It wouldn't be a drug that I would be
inclined to prescribe for someone with an addiction history.
DR.
KATZ: So, maybe the first part of your
question or statement is worth discussing, which is whether the
modified-release opioids have a higher abuse liability or risk of harm should
they be abused, or something like that.
If so, does that imply some differentiation in how they should be
used? You are suggesting perhaps in high
risk patients that is one area of differentiation and maybe there are other
areas of differentiation as well, but it seems like in either case it hinges on
the notion of whether these medications do have a higher abuse risk than the
immediate-release dosage forms.
DR.
CIRAULO: Yes.
DR.
KATZ: Maybe we should discuss that. That seems to be a relevant issue to the
current question. Do people have
comments on whether these modified-release dosage forms have a higher abuse
risk than the immediate- release forms?
Dr. Maxwell?
DR.
MAXWELL: Well, yesterday we had a
significant amount of data presented showing increases in the emergency room
episodes and treatment admissions with the introduction now at least of
OxyContin. I think some of these
increases are due to that.
What
we haven't talked about, which concerns me, is not the pain patient who, I
agree, needs the medication but the unintended consequence of creating another
pool of patients who are addicted drug users who previously were not addicted
until they used OxyContin. So, I think
we need to look at what are the unintended consequences. It is not just a new and better medication
for patients who need it, but we have created a whole new population of users
and we are paying the cost because we are now having to provide drug treatment
to this group. So, there is another
aspect to this.
DR.
KATZ: So, there is one question in the
air, which is are these modified-release forms a higher abuse risk than the
other forms? You have also echoed
another of Dr. Ciraulo's questions, which is what is the incidence of creating
new patients with the disease of addiction based on therapeutic exposure to
these drugs? I think both of you were
asking that question and implying that these are important things we need to
know in order to create appropriate standards of practice. Dr. Strom?
DR.
STROM: I think it is important, looking
at the data that we saw yesterday, that we realize that almost all of it was
numerator data. We saw a lot of
increased abuse, illness, admissions and so on, but the denominator data were
increasing equally dramatically. There
was also a lot of increased use of these sustained-release drugs and it is not
at all clear to me from the data that we saw that that indicates a higher abuse
potential. In fact, OxyContin represents
a very small proportion of all of the abuse that is out there. So, it is important to look not just at the
numerator data but also denominator data before drawing any conclusions.
DR.
KATZ: Dr. Dworkin?
DR.
DWORKIN: It seems to me there is another
way of addressing Dr. Jenkins' question in relation to whether the
modified-release opioids are associated with greater abuse liability, and that
is whether there are any data in head-to-head comparisons of modified release
with immediate release to suggest a benefit on any endpoint of the modified
release.
I
have been perseverating on that issue because I don't know, other than a kind
of broad overview of the data, the real results. It seems to me those must be incredibly
difficult studies to do because if you do it in a double-dummy way you lose the
convenience of the modified release because every patient is taking both drugs
p.r.n. or q.i.d., and if you don't do it in a double-dummy way and patients and
investigators know whether they are doing b.i.d. dosing or q4 or q6 dosing, it
is not a double-blind trial. But it
seems to me that that would be a very important set of data to know about, if
it exists, and if we could get over these methodological issues because I hear
your question as asking are there any benefits in the literature of modified
release versus what we had before in 1995.
And, I just don't know the answer to this question but I despair that
the studies can be designed in a way to really answer it.
DR.
KATZ: So, you are asking yet a third
question which we are getting on the table.
We are getting all these questions and no answers from this committee. But your third question is what is the
evidence base for the benefit of the modified-release opiates over
immediate-release opiates. Dr. Shafer?
DR.
SHAFER: Thank you. Let me just read here from Jim Zackney,
"Drug and Alcohol Dependence," 2003, this is a consensus statement
from the College on Problems of Drug Dependence: At present, it is almost impossible to
separate the risk of abuse from the therapeutic action of opioids. So, hopefully, there is one answer.
By
the way, I put the same question to Art Lipman yesterday, is there any
difference between the therapeutic action in terms of potency and abuse
potential, and he also said absolutely not.
So, the answer to that question by two people who are quite expert and publish
here is, no, there is no difference in abuse potential related to the molecule
per se. Now, there may be differences in
prescribing patterns, variability and things like this and, you know, street
fads but the pharmacologic answer appears to be no.
DR.
KATZ: As you said though, that doesn't
really get to the question of if there are any differences in the abuse
liability of the modified, high potency formulations we are talking about. It is the molecule part of the question that
that seems to be addressing.
DR.
SHAFER: Interestingly, as you pointed
out, people have associated rapid blood-brain equilibration with abuse
potential. People like the sense of
giving a drug and, whoosh--you know, you are high immediately. I infer from what I have read about these
drugs that they are intended to get around that, to not have this rapid
onset. Actually, they have lower abuse
potential. The fact that these drugs
appear to have been abused more is in line with their overall properties rather
than their pharmacokinetic profile suggests, that there is no difference one
way or the other. Certainly, the benefit
that was envisioned for slow onset was not appreciated.
DR.
KATZ: It is time for our sponsor
presentation but just for me to wrap up our collective wisdom for the moment,
it seems that in attempting to discuss the role of modified-release opioids as
distinct from other opioids at the moment we have basically three questions on
the table and we have constant pressure, as we should, to make sure that our
answers are evidence based or at least that we should understand the
difference.
One
question is whether the modified-release opioids have higher abuse risk, abuse
liability, and I am deliberately being vague about what term I use, than the
other opioids and that seems to be still a question on the table which,
hopefully, we can get back to later.
The
second question is what is the incidence of new addictions based on medical
exposure to these medications, and that remains a question.
The
third is an even larger question perhaps, which is what is the benefit of these
medications over previous forms and what is the evidence base underlying the
notion that there is a benefit?
Those
are questions that the committee has not gotten to trying to answer yet. Any FDA comments prior to moving on to the
sponsor presentation?
[No
response]
Well,
our first presentation then, if everybody is ready, will be from Dr. David
Haddox who will be speaking with us on Palladone capsules for the management of
persistent moderate to severe pain in opioid-tolerant patients. Dr. Haddox is a long-standing contributor to
this field and is currently vice president of health policy at Purdue Pharma
L.P.
Sponsor Presentation
Palladone Capsules for the Management
of Persistent
Moderate to Severe Pain in
Opioid-Tolerant Patients
DR.
HADDOX: Thank you very much, Mr.
Chairman. Members of the committee, the
members of the agency who are here, thank you for the opportunity to address
you this morning.
[Slide]
I
want to go over some of the highlights of our risk management program for
Palladone capsules and sort of bring to focus some of the issues that are in
your briefing document. It will come as
no surprise, given the discussion yesterday, that we, at Purdue, believe that
we have some considerable experience in risk management with modified- release
opioids and I would like to share how our thinking is evolving there.
[Slide]
The
speakers in this one-hour session will be myself, Dr. Sidney Schnoll, who is a
noted addiction expert and researcher, and Dr. Herbert Kleber, who is also a
noted expert in substance abuse treatment and research and is also the former
deputy director for Demand Reduction in the White House Office of National Drug
Control Policy.
For
those of you who don't know me, just a moment about myself. As you can see, I started out my professional
life as a dentist. I then went to
medical school. I have done combined
residency in anesthesiology and psychiatry with the idea of becoming a pain
physician. I have also received
certification in addiction medicine along the way.
[Slide]
In
addition to the three speakers, we have three of our consultants with us, Dr.
Theodore Cicero, who is vice-chancellor for research at Washington University
and one of the principal investigators in our signal detection component; Dr.
James Inciardi, from the University of Delaware, also a principal investigator
on another component study; and Dr. Richard Dart, from the University of
Colorado and the Rocky Mountain Poison Control and Drug Center, who was another
principal investigator.
[Slide]
You
have been exposed to a lot of material.
I heard some comments during the discussion yesterday that it seems to
be somewhat overwhelming; I hope you have had your coffee this morning. I will try to pace you through this and, hopefully,
keep things on track.
I
am going to make a few introductory comments and then I am going to briefly
review Palladone capsules as a specific drug product for you, then go through
the risk management program, highlighting our goals and objectives, some of the
elements, and giving you some examples of some of the tools that we are
using. Then Dr. Schnoll will talk to you
in some detail about the surveillance component, the RADARS system and,
finally, Dr. Kleber will end with his observations from his 35-plus years of
drug abuse treatment and drug control policy, and make some observations for
you.
[Slide]
Our
position on risk management programs for opioid analgesics is that, first and
foremost, they must protect patients. We
must try to mitigate the risk of using these medications in the specified
population for the specified indication.
We must always balance the legitimate needs of patients against the
risks posed to abusers.
We
believe that risk management programs are needed for all opioid
analgesics. We believe that they must be
consistent within a schedule of the controlled Substances Act. That is, Schedule II risk management programs
should have certain common elements and Schedule III programs should have
certain common elements.
It
is extremely important in contemplating this, given the environment into which
new opioid analgesics will be introduced, that we think about three distinct
populations, patients who have a need for and deserve good pain care; abusers
who need to be prevented, if at all possible, before they become abusers and
certainly need treatment once they become abusers; and criminals who prey on
the abusers who need to be stopped.
[Slide]
We
further believe that no single group can implement an effective risk management
program for opioid analgesics that addresses all three populations. This is a shared responsibility that requires
a multifaceted effort of coordination, cooperation and consistency from
industry, from regulators at the federal level and also at the state level as
in licensing boards, and all the other stakeholders here. Part of what I would like to do in the
presentation is show you how we have worked thus far with our ongoing risk
management program with some of these various stakeholders.
[Slide]
Now
let me briefly review for you Palladone capsules.
[Slide]
You
have heard the discussion today and yesterday that oral opioid analgesics are
an effective therapy for appropriately selected patients; that modified-release
opioids have been proven safe and effective in those patients. However, due to variability of response to
opioids and the need for individualized treatment strategies, healthcare
professionals need a variety of opioid formulations.
[Slide]
Palladone
capsules, in our approvable letter of September, 2002, were deemed to be safe
and effective by the agency. They
contain lots of little hard pellets, each of which has hydromorphone
hydrochloride embedded in an extended release matrix. That is, if you pull a capsule apart and
these little pellets fall out, each of those is its own extended release
delivery system, in contradistinction to OxyContin for instance.
Hydromorphone
is a full mu agonist with reported equianalgesic potency compared to morphine,
ranging from 1:3 to 1:10 by the oral route.
There is a great deal of variability.
It is formulated for once-a-day administration and it is going to be
launched in a variety of strengths to allow easy titration for the physicians.
[Slide]
The
benefits of Palladone capsules provide the healthcare professionals with an
important therapeutic option. It will be
the only extended-release hydromorphone in this country. The once-a-day administration is for the
convenience and compliance, for instance, the elderly patient who might have
difficulty remembering when to take medications and needs, like my mother, to
have my sister call her and say, "hey, mom, did you take your medicines
this morning?" For analgesia she
just needs that one phone call.
It
provides a choice among extended-release opioids. You have heard some comments today and pain
clinicians on the committee know that when we are treating patients, as I did
for much of my professional life, not everyone responds to everything the same
way. We need to have a large pallet at
our disposal to make sure that we can optimize care for a given individual.
The
contents--as I mentioned before, the capsules can be pulled apart and the
contents, little pellets, can be sprinkled on soft food. Think of the advantage in the case of a
person with swallowing difficulty, a person with scleroderma for instance, or a
person with esophageal stricture or radiation results from head and neck
surgery, this is going to be a real advantage for these people.
And,
it may just simply be the best choice for some patients, as was validated in
our clinical trials where we had a number of reports from the investigators
saying that this was really the right drug for that patient.
There
is less fluctuation in blood levels compared to immediate-release hydromorphone
and I will show you a PK slide.
There
is no food of pH effect, which is a distinct benefit. We have studied this in cancer and non-cancer
pain in doses ranging from 12 to 500 mg/day.
[Slide]
At
steady state Palladone, which is in the yellow here, compared to the equivalent
daily dose of immediate- release hydromorphone given, of course, several times
a day, you see lower peak-to-trough variability, essentially a smoother curve
as one would expect from a modified-release formulation.
[Slide]
I
now want to talk about the risk management program itself. It is important again to remember the thesis,
that we want to have the benefits for the intended patient population for the
intended indication balanced against the risks not only for the intended
population but also for these unintended populations.
You
will also notice as I go through this, keeping in mind those three groups,
patients, abusers and criminals, that there are Palladone-specific elements to
this risk management program even though there are also common elements with
our OxyContin risk management program because the common elements are to
address the abusers and the criminals because these are system-wide problems;
they are not limited to a single drug or formulation. The Palladone-specific elements are to
address the intended population for this particular formulation.
[Slide]
As
was mentioned yesterday, Research!America has come up with a pool very recently
showing that despite the fact that we are in the congressionally determined decade
of pain control and research, if you look systematically at the surveys of pain
prevalence, particularly under-treatment of pain in this country, not much has
changed in the last 15 years. Yet, while
Palladone will be one of the tools to help meet this need in appropriately
selected patients, it will be entering into an environment that we have already
heard a lot about yesterday.
[Slide]
These
are the number of new or first time non-medical users of pain medicines. You can see here that from 1980, just in
five-year increments, there was a significant problem in the '80s, that the
problem doubled between '90 and '95 and doubled again between '95 and 2000.
[Slide]
It
is also known from these data that, if you look, there is not one single opioid
that seems to be the problem, or even one single formulation of the branded
hydrocodones compared to other hydrocodones.
[Slide]
It
is also critical, when you are looking at these data in your briefing document,
to make sure that you follow the somewhat peculiar or at least particular way
that these data are presented and that lifetime prevalence is in response to
the question "have you ever, even once in your lifetime used a drug that
was not indicated for you or wasn't prescribed for you or for the feeling it
caused?" "Past year"
gives you an example of sort of point prevalence over a year and "past
month" is defined or is thought to be the proxy for current use. So, these are very different figures and I
just want to call that to your attention because it is easy to get lost in
these data.
[Slide]
As
part of our risk management program, in addition to reviewing these various
surveys, we have also done some analysis where we asked for specific data
runs. I just want to share with you this
analysis looking at the people who admitted to any lifetime non-medical use of
hydromorphone compared to those who said, "no, I've never non-medically
used hydromorphone."
What
you see here on three parameters over three years, '99 to 2001, is the percent
using multiple prescription analgesics non-medically--and multiple means two or
more--is about twice that in the group who admit to non-medical use of
hydromorphone than those who do not admit to that use. Likewise, the percent using cocaine or heroin
is about twice as many. If you look at
the percent using needles, it is about 12 times as many people who say that
they have any lifetime use of hydromorphone admit to needle use as opposed to
those who do not have any lifetime use of hydromorphone.
I
believe that this is describing a distinct population that is very different
from the patients that most of us are treating in a pain setting. These are people that are hard core drug
abusers.
[Slide]
Let's
talk about the pharmacological considerations for abuse liability of
hydromorphone. When you look at the
pharmacological profile, the propensity to induce tolerance, the propensity to
develop physical dependence, it looks like morphine. When you look at the human and animal abuse
liability studies, hydromorphone looks like morphine. There is no evidence in the scientific
literature of differential abuse liability among full mu agonists and
potency. As has been discussed this
morning and a little bit yesterday, it is really irrelevant to abuse liability
because the abuser will take the dose that they want, whether they take a
little or whether they take a lot.
[Slide]
Specifically
hydromorphone abuse liability, if you look in patients there is really no
evidence in the literature of differential abuse liability compared to other
full mu agonists. If you look in the
abusing population there is no evidence of greater abuse liability compared
with morphine. In fact, Preston and
Jasinski, in a 1991 review article of this literature, stated "in all of
the studies the profile of subjective effects of hydromorphone were similar to
those previously reported for morphine."
Of course, hydromorphone is a full mu agonist and in the abuse setting
has all the risks of abusing any other full mu agonist, especially the risk of
overdose and particularly when the abuse involved multiple drugs.
When
studying drug abuse deaths it is imperative to remember the caveat in the DAWN
medical examiner's report that states "when multiple drugs are involved in
a single case, the cause of death cannot be attributed to any particular
substance."
As
our recent study in the Journal of Analytic Toxicology earlier this year
showed, in 919 drug abuse deaths where oxycodone was detected, 96.7 of them
involved multiple drugs, with a mean of 4.5 drugs of use per decedent and a
range of 1-14 drugs.
[Slide]
These
data are combined from two separate studies that we have done. One was an intravenous study and one was oral
immediate-release hydromorphone single dose versus Palladone single dose. For the immediate release study, I want to
call your attention to this, this part of the curve is missing. That is because in this particular study
design, because of what we were looking for, the data point was at 30 minutes
so, obviously, this peak was much higher in the first few minutes but that is
why the data point starts right there.
This is the immediate-release and this is the extended-release
hydromorphone.
[Slide]
In
the risk management program our goals are basically three: to ensure proper
use, that is the patient population; to reduce abuse in the abusers and
potential abusers; and to minimize diversion and the attendant criminal
activities that go along with that.
[Slide]
I
would like to review for you the objectives of each of those goals. To ensure proper use, proper patient
selection is one of the key objectives.
We want to make sure that physicians know who is right for this drug and
who is not. Once they have made the
selection, we also want to know that they actually know how to use the drug,
and we want to make sure that they know how to prevent unintentional exposure.
[Slide]
As
far as reducing abuse, we are involved in a number of community-based
interventions, which I will share with you, and healthcare professional
education. We need to make sure that our
healthcare colleagues understand the signs, symptoms and indicators of abuse
and how to assess for abuse before putting a person on this medication.
[Slide]
To
minimize diversion we are supporting law enforcement in some ways that I will
give you some examples of. We have a
very active supply chain integrity program to ensure that the program integrity
is what is supposed to be as it leaves us and goes to the distributor. Again, healthcare education to help the
healthcare individuals who are prescribing and dispensing these medicines
understand what the criminal element is up to so that they can, hopefully, not
fall victim to the scams.
[Slide]
These
are some of the key elements of the risk management program. You have heard about Schedule II
restrictions. I have mentioned briefly
the supply chain integrity. Because this
is a public hearing I don't want to talk in any more detail about that because
I really don't want to tell people how to try and compromise our supply chain integrity.
[Slide]
So,
let's focus on communication of key safety messages. There are a number of things that I want to
highlight for you in this regard--
[Slide]
--the
package insert for the prescriber or dispenser, the patient package insert for
the patient or caregiver, medical communications that are outside the package
insert and our promotional activities.
[Slide]
Let's
focus on the proposed package insert.
These are some of the key elements in it. Again, in the interest of time I am just going
to highlight three. You heard about the
CII designation yesterday; you know what that involves. I want to walk you through the boxed warning
that we have proposed to the agency because I think this is the first thing the
practitioner is going to see; this will be in the ads, etc.
[Slide]
Palladone,
or hydromorphone hydrochloride extended-release, capsules are indicated for the
management of persistent moderate to severe pain in patients requiring
continuous around-the-clock opioid analgesia for an extended period of
time. Palladone capsules should only be
used in patients who are already receiving opioid therapy and who require and
can tolerate a minimum total daily dose equivalent to 12 mg of oral
hydromorphone.
Thus,
the practitioner has to meet a four-tailed test for the appropriate indication
for Palladone. The pain must be moderate
to severe. It must require continuous
around-the-clock opioid analgesia because there are moderate pains that may not
require that. And, it must require that
for an extended period of time, and the patient must be able to tolerate and
require 12 mg minimum of hydromorphone.
[Slide]
The
boxed warning goes further to say that Palladone capsules are not intended to
be used on an as needed basis or as the first opioid product prescribed for a
patient.
Palladone
capsules are only for use in opioid-tolerant patients. Therefore, they cannot be the first opioid
product prescribed for a patient. Use in
non-opioid-tolerant patients may lead to fatal respiratory depression. This is very clear, right up front.
We
also go on to state that Palladone capsules contain an opioid agonist that is a
Schedule II controlled substance with high potential for abuse, similar to
morphine, oxycodone, oxymorphone, fentanyl and methadone. In addition, the high drug content in the
extended-release formulation may add to the risk of adverse outcomes from
abuse.
[Slide]
We
then go on to tell the prescriber or dispenser that Palladone can be abused in
a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or
dispensing Palladone in situations where the physician or pharmacist is
concerned about increased risk of misuse, abuse or diversion.
Lastly,
the admonition against compromising the delivery system, taking chewed,
dissolved, or crushed Palladone capsules or its contents can lead to the rapid
release and absorption of a potentially fatal dose of hydromorphone.
[Slide]
In
the indications and usage section we reiterate the fact that it is not to be
used as a first opioid or on a p.r.n. basis and we emphasize the need for
physicians to individualize therapy in every single case.
[Slide]
Let's
talk briefly about the messages in the proposed patient package insert. Again, the admonition about intentional or
unintentional compromising of the formulation, keeping Palladone away from
children to avoid unintentional exposures; letting patients know right up front
that this is an opioid or narcotic pain medicine; letting them know that these
are not for as needed use; and cautioning them to prevent against theft and
misuse.
[Slide]
Our
medical communications--we have a single telephone number, staffed around the
clock by trained healthcare professionals to provide product information for
other healthcare professionals, to receive adverse event information and put
that into our pharmacovigilance system, and to address product inquiries and
complaints.
[Slide]
Let's
talk about the promotion. We have had
discussions with various groups and individuals and we have decided that we
would launch Palladone in a phased manner.
It will initially be promoted by a subset of the sales force to a
limited group of healthcare professionals for approximately four months. During that time there will be an ongoing
evaluation of promotional message retention and understanding by healthcare
professionals by an independent third party that we will contract with. Based on what we find from that, the
introduction of the drug will gradually be expanded based on that experience
and any modifications that derive from that experience.
[Slide]
What
will we be looking for? We will be
looking for the evaluation of messages; understanding patient selection
criteria, did the practitioner get who is an appropriate candidate for
Palladone or not? Understanding dosage
and administration, did they understand this is not a p.r.n. drug; this is not
the first opioid and things of that nature?
Understanding what CII designation means and understanding how to
recognize abuse and institute practices and procedures in their practice to
minimize diversion.
[Slide]
In
summary, our phased launch program, we believe, will help ensure that
healthcare professionals understand our messages. It will enhance the quality of our
promotional activities, and we believe that this current environment dictates
that all future approvals for CII opioid analgesics should be launched in this
manner.
[Slide]
I
want to briefly go over a few examples of interventions that we have done of
educational nature, community outreach nature and law enforcement support.
[Slide]
Healthcare
practitioners learn by a variety of ways.
Therefore, we have a variety of tools available to help them learn,
including teleconferences and distance learning for the rural practitioner who
may not be able to leave her practice to get to a CME event somewhere. We also circulate guidelines from the
federation of state medical boards and from individual state medical boards in
those states to help practitioners do a better job of complying with prevailing
rules.
[Slide]
Here
is an example of another intervention that we did. The need was this, practitioners were telling
us "I want to use urine testing in my practice to screen for illicit
substances and also to ensure adherence to the treatment plan but, you know,
this stuff is not in a textbook anywhere; it's not in one place." We made a grant to the California Academy of
Family Practitioners. They put together
family physicians; they put together a group of experts and assembled this
monograph.
What
were the results of this? By request we
have now distributed over 100,000 copies of this, not to mention the downloads
from the California Academy's web site and this is, in fact, our most requested
piece of enduring material. It has such
pearls that one might not find in there that, for instance, hydromorphone is an
active metabolite of hydrocodone. Many
physicians don't know that in a clinical setting if you have a patient on
hydrocodone and you order a GC mass spec of their urine and hydromorphone comes
back you might misinterpret those results and think that they are being
non-compliant when, in fact, you are giving them hydromorphone; you are giving
it to them in the form of a hydrocodone.
Likewise,
in a medical examiner setting this is important because in a postmortem assay,
if you get hydromorphone, you might attribute the death to hydromorphone when,
in fact, hydrocodone was the cause.
[Slide]
Slide
kits of lawful prescribing, what are the principles of lawful prescribing and
how do you prevent diversion, a very popular thing. Here, again, with an external advisory board
of experts we have produced over 10,000 of these.
Then
in our second edition, which is shown here and copies of these are available if
you wish to receive them from the secretary of the committee, we revised it
with images based on feedback from the physicians--"gee, I want to know
what track marks actually look like."
So, we now have pictures of track marks and skin-popping scars.
[Slide]
What
was the need here? Mr. Joranson talked
about this yesterday to some extent, a joint program with the National
Association of Chain Drug Stores, NADD, National Association of Drug Diversion
Investigators and the Pharmaceutical Security Institute where there is an
internet clearinghouse where police officers and pharmacists can go and find
out about pharmacy robberies one by one to compare MOs and patterns and,
hopefully, spot the patterns and stop the perpetrators.
[Slide]
Tent
cards with the DAMMADDs and MAAD moms against drug dealers. We have provided seed money for their web
side, tent cards with a phone number and the URL that are placed in
pharmacies. What are the results of this
intervention? To date, 21 convictions of
pharmacy robbers.
[Slide]
Law
enforcement support, the need--law enforcement said, "gee if we stop
someone on the street and we see a bunch of pills in the car we don't know if
they're blood pressure pills or asthma pills or something they shouldn't
have." So, we were approached by NADDI
and we gave them a grant. They have now
distributed over 100,000 of these photo ID cards, and Commander John Burke who,
by way of disclosure, is a consultant for us, said "these brochures were
one of the hottest projects we've ever done."
[Slide]
The
need--how to stop altered, forged and counterfeited prescriptions. The solution--security paper. This paper has a number of security features,
including "void" appearing, as you can see faintly here. It shows up better in real life; it doesn't
project well but no matter what you have your scanner set on or your
photocopies set on, you are going to get a line of "void" across
there. It is also watermark paper. It is also sort of a water colored pattern
like your checks so if you try to smudge or alter a prescription it will be
very obvious. We have now been
distributing these free of charge.
The
results of this--a lot of physicians are using them and, secondly, a number of
states have now recommended this to physicians.
Some states are contemplating making it mandatory.
[Slide]
Public
service ads, the Household Survey data and also alerting parents to the fact
that, you know, kids find drugs in lots of places and the street is not the
only place. Know what is in your
medicine chest.
[Slide]
Communities
that Care is a structured planning system that is based on 20-plus years of
NIH-funded science research that provides strategic consultation; working with
communities to provide an integrated approach to diminish these kinds of
problem behaviors in communities. The
reason is that research has shown that these are linked. If you just go after teen pregnancy and that
is all you do, you are not likely going to make a dent if there is violence in
the school, high dropouts, etc. Likewise
for drug abuse. The CTC program which
Michelle Ridge, Tom Ridge's wife is the national spokesperson for, is working
with this and we are supporting this in a number of communities right now.
[Slide]
The
need--young people. The Household Survey
data showed that the 12-17 demographic are the ones who are the most frequent
new initiates of pain reliever non-medical use.
Targeting middle school students, the strategy was to make these
so-called "tweens" feel sorry for people who abuse prescription drugs
because they have no self-respect and dignity.
The key message is if you abuse prescription drugs you will lose your
dignity; trying to resonate to what is important to this demographic, if you
use drugs you are not cool anymore.
[Slide]
We
have done it in a way that resonates, this sort of gross-out humor:
"picking your nose at lunch does not count as dessert" and
"spastic shaking caused by prescription drug use is
creepy"--painfully obvious is the conclusion, hence the tag line for the
program. We have a web site. There have been over 300,000 hits on this web
site and over 4,000 copies of this material downloaded in addition to the ones
we have distributed in hard copy form.
[Slide]
Does
this work? We are not really sure but
there was last week, at the Household Survey press conference, an encouraging
comment by John Walters, the current director of ONDCP, that said that the data
suggest that youth who have heard anti-drug abuse messages have lower rates of
abuse than those who have not heard the messages--not a huge difference but if
my kids are in the 11.3 percent, that is where I want them to be.
[Slide]
Multi-faceted
surveillance, this is a key tenet of any risk management program. You have heard things about that.
[Slide]
Again,
monitoring for patient safety, pharmacovigilance, including a structured,
regular ongoing review of scientific literature; monitoring for other
populations I mentioned; national surveys, as I have mentioned, the ones we
have looked at and it is not passive monitoring, as I have shown you from the
special data we have from the Household Survey; also monitoring the
future. Some of our consultants met with
the people who do monitoring in the future and actually got them to modify this
high school-based survey to include issues about prescription drug abuse and
remove things that probably didn't have very high abuse prevalence, such as
laudanum.
Media
surveillance--we have an active sample through one of the clipping services
where we look at media surveillance to find out if there are reports of abuse
or diversion around the country.
Then,
the RADARS system. This is an evolving
system but it is innovative. We are very
excited about it. We think we have some
very good data. Of course, we fine-tune
as we go along, but I think it is something that you will find interesting and
for that I would like to introduce my colleague, Dr. Schnoll.
RADARS Surveillance System
DR.
SCHNOLL: Thank you very much.
[Slide]
I
am going to be talking to you this morning about the RADARS system and I would
like to reiterate something that Dr. Haddox said to you already, that this is
an evolving system. As you heard
yesterday from Dr. Winchell, there are no guideposts for how to run this type
of surveillance; there are no data out there.
We have some clues from research that has been done in the surveillance
of altram and Meridia but we felt we had to expand this system. You will be seeing some data today that were
sent to the FDA but they have not had the opportunity to comment on those data
at this time.
[Slide]
We
had picked up the media indicating that OxyContin abuse was becoming a public
health concern. We recognized that we
did not have the expertise to deal with this on our own and so we put together
a panel of outside experts to assist us in dealing with this situation. This external panel, the external advisory
board, was formed in June of 2001, and part of what they did was to review
existing databases. They recognized from
these reviews that the data in these databases was often not timely, being
published or presented sometimes a year or more after the data had been
collected, and the data were not necessarily geographically specific. What we were hearing and seeing was that the
problems of prescription drug abuse were not uniform nationally but seemed to
have specific target areas around the country.
So,
the programs that were developed in RADARS were developed to provide
geographically specific and timely data.
The question came up yesterday about whether or not these data were
presented to the FDA, and I would like to mention that on June 23 we had a
meeting with the FDA to present RADARS data and the FDA, and other federal
agencies, do meet with the external advisory board on a quarterly basis to
review what is happening with the RADARS system.
[Slide]
These
are the members of our external advisory board.
As you can see, there are many well-known researchers in addiction,
people who are in policy positions regarding prescription programs and law
enforcement.
[Slide]
The
goals of the RADARS system are primarily to study the nature and extent of
abuse and diversion of scheduled prescription opioids, and you see the drugs
that we are studying here. These are
major and important Schedule II and III prescription opioids. In addition, the goal of the external
advisory board and the RADARS system is to develop and suggest to Purdue
interventions to reduce both diversion and abuse.
[Slide]
The
objectives are to proactively collect timely and geographically specific data
on the abuse and diversion of the drugs you have previously seen.
In
addition, as has come up here already by Dr. Strom this morning, there is a
need to develop rates and we need to develop these rates both on a national and
a local level because, as I mentioned, problems do not exist uniformly across
the United States.
In
addition, we have to develop interventions and these interventions are
suggested at times by the EAB and are done in collaboration with Purdue to
reduce the diversion and to monitor the outcomes of these interventions.
In
addition, we review existing databases, such as you have seen with the National
Survey of Drug Use and Health, to do some other analyses of these databases and
review the literature to look at new data as they are emerging. We see what we are doing with RADARS as
complementary to these existing programs.
[Slide]
There
are several levels of activity involved in the RADARS system. Signal detection is the first one we do, and
I am going to go over some of the data from our signal detection systems.
From
signal detection the data are then taken and merged and they are sent to the
Johns Hopkins University where relative rate determinations are done, and I
will discuss that a little further later on.
When
we receive a signal that we feel is at a level that requires something to be
done, we go in and investigate that signal and do verification as to what that
signal means. We may get data from other
sources at Purdue which will launch a signal verification.
The
three bottom items, the focused studies, interventions and outcomes, will
depend on what happens with that signal verification and so don't always occur.
[Slide]
The
signal detection component functions as an early warning system. As I have mentioned already, the data are timely
and you will see that as we already have second quarter data from 2003. They are geographically sensitive and we can
break the data down to the first three digits of the zip code. This makes it very useful for monitoring
localized outbreaks of an event that may occur with a newly approved drug. The threshold we have set for signal
verification is five or greater cases per 100,000 population in that
three-digit zip code. We feel that that
is a very sensitive level and this may be from a single detection study or from
a combination of all of the signal detection studies.
[Slide]
The
signal detection studies are funded by Purdue.
The studies, as you will see, are conducted at major universities under
the direction of a principal investigator, and the data are independently
housed at those universities and reported to the external advisory board and
Purdue on a quarterly basis.
[Slide]
Through
the signal detection studies we have covered a wide area of the United
States. If you look, there is the Key
Informant study with the stars; our Drug Diversion Network, with the diamonds;
and DENS Network, with the yellow circles and these are the states that are
either wholly or partially covered by the Poison Control study. So, we have a rather significant area of the
United States covered with these studies.
[Slide]
The
principal investigator for the Key Informant Network is Dr. Ted Cicero who is
with us today. The key informants are
made up of pain specialists, NIDA grantees, drug abuse specialists and others
who can provide information to us in their local area about what is going
on. We have picked one three-digit zip
code to present some data to you to show the kind of data that we can collect.
[Slide]
As
you will see, the data cover a range of drugs and I think it is important to
point out that this is a very sensitive system and we are able to detect
already abuse of buprenorphine, a drug that does not have a lot of
prescriptions at this time. But we can
see changes over time in what is happening with the various drugs on which we
are collecting data.
[Slide]
The
law enforcement drug diversion signal detection study is under the direction of
Dr. James Inciardi, at the University of Delaware, and he is collecting data
from drug diversion units around the United States. As you can see, we are continually trying to
increase the number of key informants and units from which we are collecting
information.
[Slide]
These
are the sites that have responded in each quarter. These are the number of cases that they are
reporting. We have consistent response
from about 85 of these sites each quarter, and there is a group of about 85-90
key informants who respond to us each quarter.
[Slide]
In
each of those cases there may be several drugs mentioned. Here is the data from the four quarters of
2002 and up to 2003 second quarter, and you can see there is wide variation in
the diversion of different prescription drugs, and we have some benzodiazepines
included here. Hydrocodone is the most
commonly reported. OxyContin, which is
separated from other oxycodone products, appears to be dropping a little bit
over this time but, as has been reported in the press, we are beginning to see
some increase in methadone mentions.
[Slide]
Yesterday
you heard Dr. Winchell mention the Drug Evaluation Network System that is under
the direction of Dr. Tom McLellan at the University of Pennsylvania. The important part of this system is that it
collects data on a real-time basis. In
some of the other systems you have heard about the data are collected, say,
once a year and then the report may not occur for some time.
[Slide]
These
are data on 11,000 consecutive admissions to the programs in the DENS
system. There are about 80 programs
nationally, some in urban areas and some in rural areas. As you can see, again hydrocodone is the most
frequently mentioned drug. There are
specific questions asked about these drugs in the DENS interview, and
hydromorphone is also picked up.
[Slide]
As
you see again, we can plot over time what is going on with these drugs. This is lifetime reported use of
hydromorphone and this is past 30-day use, as Dr. Haddox mentioned, which is a
surrogate for recent current use. I
would like to point out the scale here.
This only goes up to 3.0 so this is not a major rise in the problem.
[Slide]
We
are also collecting data from poison control centers. One of the most important things about the
data from the poison control centers is the fact that the people who are
collecting the data give very specific information about what the tablet
is. They ask about what the markings are
on the tablet, the size, the shape, and they can then look at a book that gives
them specific information and say precisely what branded or unbranded drug was
being reported.
[Slide]
This
is a map showing, in our pilot study, the coverage we have from the poison
control system. It covers over 25
percent of the United States and, as you can see, covers some of the states
mentioned yesterday as areas with high problems, Kentucky, Virginia, Maine, and
we are trying to expand this system gradually to include more of the United
States.
[Slide]
There
are two types of calls that come in to the poison control centers. One is an information call where somebody may
have forgotten what their pills are. As
you know, many people will put all their pills into one little box and then
they can't remember so they may call to find out what a specific pill is, or
somebody found a pill. But the ones we
are most interested in are the intentional exposure calls. These are the calls when somebody has taken a
drug either for abuse problems or for suicide.
As
you can see, these are data from all of the poison control centers from which
we collect data combined and we have worked at a rate per 100,000 based on the
population covered by those centers.
Again, you can see hydrocodone here, oxycodone--this does not include
OxyContin which is covered separately--and the other drugs involved.
[Slide]
Now,
the data that are collected from these signal detection studies are then sent
to Washington University where we have a central database housing all these
data. The data are collated and then
specific data fields are sent to Johns Hopkins University where rates are
calculated.
Now,
as I mentioned earlier and Dr. Strom has brought up, the denominators are very
important in calculating these rates. In
looking at this, it is clear that there is not one simple denominator to use to
provide us with the information we need.
If you are going to look at patients you have to look at patient day
exposure. A short-acting opioid may only
be used for 10, 11 days. An
extended-release opioid, such as OxyContin, may be used for 24 days so you have
more exposure and you may have a higher dose.
You
also need to know how much drug is out there, kilograms sold. If you are just looking at prescriptions you
may get data that are biased because IMS data provides prescriptions mainly
from retail pharmacies and currently, for a drug like hydromorphone, there is a
significant portion of that drug that is being dispensed in hospitals and
long-term care facilities those are not included in the IMS data. So, unless you are aware of that you can get
a skewed rate so there are many different types of denominators that we have to
look at to find out which is the most appropriate to provide us the information
that we need.
Using
these denominators we are trying to calculate relative rates of abuse and
diversion of the drugs that we are investigating, and with this we can compare
one drug to another and compare a drug to itself over time to look at changes
in the rates.
[Slide]
To
give you an example, we have looked at DAWN data and created a rate based on
total kilograms sold. This is not just
the kilograms dispensed in retail pharmacies but the total kilograms including
hospital and other sources. As you can
see, there is some consistency of those rates.
OxyContin has gone up. This is
morphine, in the purple. We do not have
the 2002 OxyContin data yet since the DAWN data were just released and we have
to obtain the specific data from SAMHSA to get that.
[Slide]
Once
we pick up a signal, as I mentioned five or greater cases per 100,000
population in a three-digit zip code, we have our field researchers go in using
a questionnaire that is structured to try to verify the nature of that signal. This is very important because we are finding
that there are different problems going on in different parts of the
country. We have recently investigated a
problem in a tribe of native Americans in the northwestern part of the United
States where the problem appeared to be drug being smuggled in from
Canada. In another part of the country
we found that it was a city, 20,000 people, a lot of nursing homes and assisted
living facilities and 18 pharmacies for 20,000 people. In a third area we discovered that river boat
gambling had moved into the area and brought in a lot of outsiders who were
using drugs.
If
you look at these differences, it tells you that there is not one single approach
that can be applied on a national basis for these various problems, and that is
why we need geographic specificity in terms of what we are doing. As mentioned here, the results of these
interviews are presented to the EAB for suggestions on where to go.
[Slide]
I
mentioned the focused studies. We have
two focused studies that are currently going on, one in southwestern Virginia
under the direction of Dr. Janet Knisely at Virginia Commonwealth University,
one in Maine under the direction of Dr. Heimer at Yale University, and we are
soon to implement a third in eastern Kentucky under the direction of Dr. Carl
Leukefeld at the University of Kentucky.
So
far, information from these studies has pointed out that, one, it is very
difficult to collect data from people in rural areas. They are very reluctant to talk to outsiders
who come in to try to gather information from them. But we are also discovering that prescription
drug abuse has been endemic in these areas for a long time and people go from one
drug to another. So, we are getting some
very important information.
[Slide]
Based
on the information we get, we will be developing, in conjunction with the
external advisory board, interventions that are specific to the area. In one case we found a physician who was
performing some illegal activities and that was reported to the local
authorities. As I mentioned, the
interventions are specific. Dr. Haddox
has gone over some of the interventions that the company is already doing.
We
need to look at outcomes for these interventions, and we will monitor carefully
with our signal detection studies to see if there is a change but we will also
look at other indicators.
[Slide]
So
far, we have learned something about prescription drug abuse from the RADARS
system. One, that abusers of a given
opioid drug are similar to abusers of other prescription opioids. There seems to be no specificity in terms of
the abusers. These individuals are
typically individuals who have abused other prescription drugs as well as
illicit drugs. This is not a problem of
ethnic minorities and, as mentioned, the problem seems to be endemic in some of
these areas.
[Slide]
We
feel, in summary, that the RADARS system establishes a standard for proactive
collection of data on abuse and diversion and provides relative rates of abuse
and diversion for the drugs of interest.
We are able to detect abuse and diversion of the drugs that are
infrequently prescribed, as pointed out by buprenorphine, and the data are
generated in a geographically specific area and in a timely fashion.
I
would like to now turn the microphone over to Dr. Herbert Kleber.
Prescription Drug Abuse
DR.
KLEBER: Thank you for the opportunity to
meet with the committee today.
[Slide]
I
would first like to point out this is not a new problem. Prescription drug abuse has been with us for
a very, very long time. The
under-treatment of pain has been with us for a very, very long time and the
question is always the tension between these areas. How do we keep effective pain relievers
available for appropriate medical use while decreasing abuse? If I stood up here and said we have the
answer I think you would all get up and walk out, and rightfully so. This is an evolving area. There is no one answer yet. We are improving what we do; we don't have
the answer.
[Slide]
At
the turn of the century we had an enormous problem with patent medicines. They were often unlabeled. One of the favorites was Mother Winslow's
Soothing Syrup which was rubbed on the gums of teething babies and also taken
by the mothers when they had trouble dealing with the teething babies. Finally we had the Pure Food and Drug Act in
1906 which at least required that these patent medicines be labeled as to
ingredients. It certainly did some
good. On the other hand, it left a lot
of openings. You still had doctors and
pharmacists who were basically willing to sell these medications to whoever
wanted them, and you had mail order catalogs.
So, there is really nothing new under the sun, today we have the
Internet drug sales; in those days you had mail order catalogs.
Then,
in 1914 the Harrison Act tried to close some of these loopholes and you needed
prescriptions by physicians for reasonable treatment of pain. At the same time, as often happens with
unintended consequences or maybe intended, basically between the Act and the
Supreme Court interpretations, it ended the involvement of the general medical
system in the treatment of addiction. It
stayed that way really until methadone came along, and you will hear more about
that from my colleague, Dr. Kreek, this afternoon.
[Slide]
The
Harrison Act did not solve the problem of prescription drug abuse. We keep trying to do it by coordinating
things better. The last bullet there,
ONDCP, is one that you have heard. I had
the honor to serve as the first deputy director, back in 1989, under Bill
Bennet and the first President Bush.
We
keep trying to improve things, not just with coordination and with laws
regulating prescribing, but with enforcement activities so the Bureau of
Narcotics morphs into the Bureau of Narcotic and Dangerous Drugs, which morphs
into the Drug Enforcement Administration.
Each probably is somewhat of an improvement over what came before but is
clearly still problematic.
[Slide]
Who
are the abusers? I have been in the
field for between 35 and 40 years and it has been my experience that there are
really four groups of people that we need to talk about. We need to talk about addicts. We need to talk about pain patients. We need to talk about addicts who have pain,
and we need to talk about pain patients who become addicts. Each of these is a different category. They need to be approached as individuals, as
is beginning to emerge from the discussions this morning, especially as Dr.
Baxter pointed out that we need to keep in mind that there is no one approach
that is going to work for all of these, but most non-medical users of
prescription opioids are polydrug abusers.
These are not people who just abuse these medications; they also tend to
abuse alcohol, marijuana and other drugs.
Most pain patients do not abuse these medications nor do they become
addicts. There aren't as good studies as
we would like, especially prospective studies, but most studies of the few that
we have suggest that it is less than five percent of people who receive
legitimate medications for pain end up addicted--not dependent, a different
term, but addicted.
[Slide]
Since
the patient is not the key person at risk for prescription drug abuse, how much
legitimate medical need needs to be tolerated to reduce abuse? Again, it is that tension that we have talked
about that there is no easy answer to.
[Slide]
So,
let me wrap it up in the next minute or two.
Quick fixes do not work for complex problems. I wrote in an op ed in "The Times"
15 years or so ago that we should leave the quick fixes to the addicts. There is no easy solution.
There
are often unintended consequences of good intentions. The concern over OxyContin led many
physicians to stop prescribing it and many pharmacies put signs in their
windows saying "we don't prescribe OxyContin" and it led, instead, to
a marked increase in prescribing of methadone for pain relief and more
diversion of methadone, which then has also the unintended consequence of
casting disrepute on legitimate methadone maintenance programs.
So,
when you squeeze the balloon in one part it tends to pop out in another, often
in areas where you don't expect it to.
The patterns of drug abuse continually shift and preferences
change. In the '70s Quaaludes was a big
problem and we haven't heard about that for quite a while. PCP was also a problem and this stayed with
us.
We
continually search for technological fixes.
One of my favorites was paregoric, which was camphor with a tincture of
opium. The camphor was put in to deal
with abuse. One of the first things my
addicts taught me, when I was at Lexington treating patients there in the early
'60s, was you simply take the paregoric, put it in the freezer, the camphor
freezes, the tincture of opium doesn't.
You throw away anything that freezes, boil what is left and you now have
opium. So, the addicts are very good at
figuring out whatever system we come up with.
Likewise, the Addiction Research Center which is now the intramural
branch of NIDA, was really set up in the '30s with one of its major missions to
come up with a non-addicting analgesic, a strong analgesic, and we are still at
it, guys. But, hopefully, maybe before
the Red Sox beat the Yankees and win the pendant--remember, I spent most of my
years in New Haven so I am a Red Sox fan, not a Yankee fan.
So
we continue to search for technological fixes.
We have certainly come up with better ones but I have great faith in the
ability of true abusers to get around it.
So, I expect evolutionary, not revolutionary, changes.
[Slide]
We
have a number of strategies that have we have gone over. I am not going to reiterate them; you have
heard about them. I have been associated
with the RADARS program since its inception in July of '01, and in my
experience in treatment of addiction, treatment of pain, the risk management
strategy that is used for OxyContin and Palladone and the RADARS part of that
strategy is one of the most comprehensive I have ever encountered. Is it perfect? Absolutely not and that is why they have all
these experts on the committee to try to keep tweaking it to improve it.
[Slide]
Secretary
Thompson has just recently commented on the need for treatment. "There is no other medical condition for
which we would tolerate such huge numbers unable to obtain the treatment they
need." Again, if many of these
people who cycle through the system could get adequate treatment for their
opioid problem there would be much less of a difficulty out there. With heroin, for example, less than 20
percent of the individuals who need treatment are getting it.
[Slide]
Last
slide, and this I think is a really important take-home message I want to leave
you with, the past decade has witnessed the pendulum swinging toward adequate
pain relief for patients. This has
occurred under the impact of legislation, of lawsuits, of reports from learned
societies. My own feeling--hopefully I
am wrong--is that this pendulum swing is still very superficial; it is skin
deep; it is easy to reverse and I think we need to pay attention to that, and
it is important that any strategies that we come up with do not reverse the
trend toward adequate pain relief for that segment of the population that needs
it. Thank you.
Questions from the Committee
DR.
KATZ: Let me thank the speakers from
Purdue and from Columbia for their comprehensive presentations. Of course, it is always tantalizing because
there are so many issues that we would all like to discuss in depth and we
never seem to be able to satisfy ourselves there, but I am sure people around
the table have questions for the sponsors and we have 15 minutes allocated for
that. So, why don't we go ahead and take
that. Dr. Dworkin first?
DR.
DWORKIN: I think this is a question for
you, David. It seems to me, in thinking
about risk management programs, that the extent of how widely the drug will be
used is a consideration so that a risk management program for buprenorphine or
transmucosal fentanyl might need to be different than for more widely used
drugs like OxyContin.
So,
I guess I would like to know--and I hope this is not an unfair question--by any
measure OxyContin is a block-buster drug. looking down the road four or five
years from now, how does Purdue view Palladone?
Is it going to be another block-buster drug like OxyContin or do you
view Palladone as being a more niche-limited used drug? There must be projections of this that your
marketing projections have done.
DR.
HADDOX: There are marketing projections
but we don't discuss commercial information in public, but let me see if I can
answer your question in a way that satisfies the need. If you look at the indication for OxyContin
and indication for Palladone, they are fairly similar with the exception of
that fourth test, that is, the opioid-tolerant individual who needs and
requires 12 mg minimum of hydromorphone.
So the estimation would be, I think logically, that it is going to be a
smaller subset of patients than those who are taking OxyContin. Now, there are some five million patients in
the entire country who might be appropriate candidates for opioids that are
high potency. So, you know, OxyContin
has a share of that. Maybe about 1.7
million patients in a given year have been exposed to OxyContin. My guess is that Palladone will be smaller
than that, but I really can't give you a scale of marketing projections.
DR.
KATZ: Dr. Crawford?
DR.
CRAWFORD: Thank you, Mr. Chairman. Dr. Haddox, thank you for the
presentation. I have three very quick
questions, at least there could be very quick answers.
First,
slide 30 with the boxed warning part of the indication states use for an
extended period of time which, of course, could be subject to
interpretation. What is the intent of
the sponsor?
DR.
HADDOX: Well, this is a claim originally
negotiated with the agency. It requires
clinical judgment. Certainly, it is not
appropriate for a day or two but it might be appropriate if the pain is going
to last for a few weeks. It is somewhere
in that range and we and the agency I think agreed, certainly with the labeling
for OxyContin, that you don't want to, you know, draw a line in sand. You want clinicians to use their judgment and
individualize therapy.
DR.
CRAWFORD: Thank you. The second one, slide 32, the capital letters
with the boxed statement not to compromise the formulation, one thing that is
very important in my opinion for us to understand is can you describe and
quantify the potential or the likelihood of adverse effects if the formulation
is compromised, as well as what the appropriate use is because we didn't see
any figures on fatalities or other serious adverse events that may occur with
the formulation?
DR.
HADDOX: I think you asked two questions
there.
DR.
CRAWFORD: That was my second question. Can you describe and quantify what are the
adverse effects, what is the likelihood of that occurrence if the formulation
is used appropriately and if it is compromised?
DR.
HADDOX: That is what I meant by two
questions, two conditions. If the
formulation is used appropriately the safety profile in all of our studies we
submitted to the agency is comparable to the safety profile of any other
opioid. We, obviously, don't try to
compromise the delivery system and give it to people and see what happens. So, we can only guess that it would be what
the warning describes, which is why we and the agency agreed to put that in the
proposed label.
DR.
CRAWFORD: Okay, and the last very quick
question, the tamper-resistant pads, do they come preprinted with the product
name or indication to the prescribers?
DR.
HADDOX: All they come preprinted with is
the prescriber's information they would normally print--name, address, that
sort of stuff. In fact, we actually
encourage prescribers, based on advice from law enforcement, not to preprint
their DEA registration number either.
So, you know, just your name, your phone number, your address, what you
would normally do. Then, because they
are distributed in different states, the vendor goes to the state board
pharmacy with a prototype and says does this meet your requirements for
prescription in this state? And, we have
had to tweak that a few times so that it would be state specific.
DR.
KATZ: Dr. Ciraulo is next.
DR.
CIRAULO: Dr. Crawford asked one of my
questions but I just would like to expand on that. Do you have data on how easy it is to
compromise the formulation to make it from a modified release to an immediate
release? Do you have PK data or toxicity
data either in animals or humans that would give us some information on what we
could predict might happen if it is easy to chew and get this into the brain
more quickly?
DR.
HADDOX: There has been some work done on
that. We don't do this in normal
volunteers, as you might imagine. It is
harder than some and it is not impossible but, again, being a public hearing
here, I don't think it is prudent for public health to discuss ways people
might compromise the delivery system.
DR.
CIRAULO: Sure, but the FDA, you have
that data?
DR.
KATZ: But, Dr. Ciraulo, is your question
what would be the likelihood of harm to some sort of person, say an
opioid-naive individual, should they be able to ingest a compromised dose or an
immediate-release dose of whatever is in one of these Palladone pills?
DR.
CIRAULO: Yes, that is my concern.
DR.
KATZ: So, if someone, for example, were
able to compromise the 12 mg tablet, just to pick a dose, and ingest that, in
opioid-naive people what is the likelihood of harm? That is your question?
DR.
CIRAULO: Yes.
DR.
KATZ: Are there answers to that?
DR.
HADDOX: Well, I think, you know, the
likelihood of adverse events is pretty clear.
Which adverse event would occur I am not certain. I am not aware of people who have done that,
who have given 12 mg of IV-push of hydromorphone to opioid-naive volunteers to
see what happens to them. Even where I
trained you wouldn't get too many medical students to volunteer for that
study. So, I think the warning is
appropriate. It says what we all believe
in my clinical experience, that if one were to compromise this, this is very
risky behavior.
DR.
CIRAULO: I think my problem is I can't
advise anybody--I can't advise the agency without knowing the toxicity data,
but you have it.
DR.
RAPPAPORT: We will have the data, we do
have the data and are able to review that but to some extent Dr. Haddox is
correct, we would expect certain severe adverse events to occur, but there is
not a lot of clinical work you can do to study that.
DR.
CIRAULO: Yes, my concern is when this
medication is on the street and gets diverted, as it will get diverted and as
addicts begin to tamper with it, what are we going to face from a public health
standpoint?
DR.
RAPPAPORT: Theoretically there could be
people dying from taking these products and abusing them, but I don't know that
we can say any more than that.
DR.
KATZ: Dr. Haddox, correct me if I am
wrong, but it sounds like we should assume for the purposes of this discussion
that the likelihood of harm for an opioid-naive individual ingesting an
immediate-release formulation of any of these dosage forms of hydromorphone
would be very high. Is that a fair
assumption?
DR.
HADDOX: I think that is a fair
assumption with any equivalent dose of hydromorphone, regardless of
formulation.
DR.
KATZ: Dr. Aronson is next.
DR.
ARONSON: Thank you. I have a number of questions. Let me ask you, Mr. Chairman, if you wish for
me to ask them all. Some are directed to
Dr. Haddox and others are directed to some of our other speakers.
DR.
KATZ: Any questions to any of the
sponsor representatives is fine.
DR.
ARONSON: Okay. This is an operational question that I would
like to direct to you, Dr. Haddox. You
mentioned a number of risk management tools that you are going to launch or
implement as you phase your launch of Palladone. Other than just telling us that there are
guidelines and brochures and CDs, etc. that you wish to promote in an
educational process, what is the metric that you are going to use to judge whether
or not that message was received, and what is the threshold that you would use
to determine whether or not you are going to accelerate your launch beyond your
first phase?
DR.
HADDOX: Let me answer that in two
parts. Number one, it is clear, as I
said before, that there are some elements of this that are Palladone
specific--the phased launch, the labeling for Palladone, etc. But the big difference between Palladone and
OxyContin is that all of these things that I have talked about, except for the
phased launch which hasn't occurred yet, are already in place. Practitioners have gotten the
tamper-resistant pads. They have been
educated on abuse and diversion. Those
things are out there.
RADARS
is up and running and that is the second part of the answer. I believe that one of the major mechanisms we
will use in the evaluation of the message will be those four points that I
talked about. The threshold is still
being determined because it is an evolutionary process. We are still trying to sort out how to do
that best. But the big metric will be
will RADARS pick up something early on and allow us to do targeted
interventions to try and suppress the issue.
DR.
KATZ: Does that answer your question?
DR.
ARONSON: I think so. I think the point is, is there a threshold
whereby you would just sort of delay or stop your process of evolving the
launch?
DR.
HADDOX: I think it would be premature
for us to try and determine threshold until we try and get some data back from
that message evaluation to see what it looks like. I think at that point we will get a sense of
what should be the cut-off or what we should do differently.
DR.
ARONSON: The segue to that--and I would
firstly say that the RADARS program, in my opinion, is responsible and you
ought to be commended for the effort, but as was pointed out by this committee,
the problem of clearly defining the denominator still persists despite your
best efforts and so I raise the question is more incomplete data better than
complete data? I suppose we are having
to confront that.
The
part of this equation that I think we need to consider, and I am asking if you
have attempted to do that, is the mirror graph, if you will, the decrease in
the number of patients that need to be treated for pain. As that decreases, as that tendency would
drop we would expect the adverse mirror curve to increase, and at one point do
the lines cross and is that the point that we find acceptable? Is there any data to show the benefit,
improvement?
DR.
KATZ: Can you clarify that question?
DR.
ARONSON: I will try. We conceptually appreciate that the reason we
would consider, if you will, approving another drug is because we wish to do
good for those people who deserve to have good done. Are we measuring the impact of how much good
we are doing and comparing that to the potential harm that may come of it? We have only seen the absolute increase in
harm but we haven't looked at that in a comparative way to the absolute good
that we have done. Are there any data to
show that?
DR.
HADDOX: Well, as I have said before, if
you look at survey data, survey data have not really changed substantially in
the past 15 years in terms of the prevalence of under-treated pain. I think, however, that the denominator issue
that you raised in the preamble is important because, as Dr. Schnoll pointed
out, we don't anticipate a single denominator.
We think that this is a complex issue and to really understand this we
may have to look at multiple denominators, some of the ones that he pointed
out, so that we can look at what is the relative risk of abuse or diversion of
one formulation to another, those sorts of questions. It still begs the question how can we measure
the benefit to the populace and that is a tough question. Outside of survey methodology, I don't have
any suggestions right now but I would be willing to entertain them.
DR.
KATZ: I want to make sure we are getting
to the core of your question. Are you
suggesting that a risk management program such as the one that is being
proposed for Palladone should incorporate a component that measures the
societal benefits of the approach as well as the risks so that we can have a
complete picture? Is that your question?
DR.
ARONSON: Absolutely. What we are confronted with is a balance of
most good for least harm, and we need to have that side of the equation in
order to make that decision and I do not see that side of the equation. So, yes indeed, I am asking that.
DR.
KATZ: And how would you suggest that be
done?
DR.
ARONSON: Give me a moment.
[Laughter]
DR.
KATZ: There is a long list; I will put
you at the bottom so you will have some time.
Dr. Cush, you are next.
DR.
CUSH: I have two questions, one for Dr.
Rappaport or the agency. Could you just
generally state what your requirements for manufacturers as far as
pharmacovigilance are and what you want them to do in their program? Some of the agency requirements for
pharmacovigilance for a product like this?
The
second part is going to be to Dr. Haddox.
Could you tell us why you chose four months and to what selected health
professionals will you be targeting initially, and is that the appropriate
population, meaning is that the population that has also been shown to be
guilty of improper use of these agents in the past?
DR.
KATZ: So, first question first.
DR.
TRONTELL: I will comment first on the
regulatory requirements for pharmacovigilance.
The regulatory requirements in that arena are uniform across all
products and require reporting to the agency of adverse events that come to the
attention to the sponsor spontaneously.
They are mandated to send those to the agency and those in a certain
category deemed serious by regulatory definition are, in fact, required to be
sent to the agency on an expedited basis.
I will defer now to Dr. Rappaport to talk about this particular class of
drugs.
DR.
RAPPAPORT: We have been asking for some
extra pharmacovigilance with this group of drugs, asking for expedited reports
that are expedited on a faster basis, and following carefully indications of
abuse, overdose and such. So, we are
doing a little bit extra here but the general requirements are what we follow
for all drugs in all areas of safety.
DR.
CUSH: So, is this risk management
program we are talking about here part of the pharmacovigilance effort?
DR.
RAPPAPORT: Yes.
DR.
KATZ: The second question was on the
specialists that are being targeted in the initial phase.
DR.
HADDOX: The intent is to have that
portion of the sales force which calls on physicians who are likely to have
patients for which Palladone would be an appropriate option. So, people like anesthesiologists, pain
specialists, oncologists, that is the intent.
As
far as the four months, we had to start somewhere. We just decided we would collect the
information. We will be looking at it as
it comes in but four months is where we will sit down and really try and make a
decision point.
DR.
KATZ: Next was Dr. Shafer.
DR.
SHAFER: Thank you. Three questions. I think they will all be pretty
straightforward. The first is a simple
pharmacokinetic question. In looking at
the data on drug administration over the first 24 hours the peak concentrations
are reached at 24 hours, suggesting you have done a very good job on the
sustained release part. But that also
suggests that over the first week of therapy there is the potential--not a
potential, the drug will accumulate until you reach your steady state. How much more does the drug level rise over
the first week of therapy until you reach steady state?
DR.
HADDOX: Two to three days to reach
steady state.
DR.
SHAFER: And how much has it risen? Has it doubled over that period of time?
DR.
HADDOX: No, I don't think so. Let me ask my clinical experts here.
DR.
KATZ: Could you come up to the
microphone, please?
DR.
SHAFER: I was impressed that the peak
was reached at 24, which means that you are then adding your next dose on top
of that.
DR.
APFEL: David, if you could go back to
the slide showing the steady state?
DR.
SHAFER: But we are really talking about
the rise to steady state, not the steady state exactly.
DR.
APFEL: My name is Dr. Stuart Apfel.
[Slide]
DR.
SHAFER: That shows the rise and what I
am referring is the peak at 24. So, the
question is how much accumulation will you get on top of that over the first
week of therapy?
DR.
APFEL: We see that the levels continue
to remain pretty much at that same level with continued exposure. As the drug is continued to be administered,
once it reaches steady state the levels of the drug in the serum remain
approximately the same. You can see it a
little bit better here where you see very little variation.
DR.
KATZ: I think the question was what is
the ratio of the blood level at day three to the blood level at day one. Is that right?
DR.
SHAFER: That is right. If we could go back because it is not in the
handout that we received. The question
is how much higher is this than the level at the end of the first day of
treatment.
DR.
HADDOX: That is why I went back to
this. There is the metric, right
there. It is a little less than 2 ng/ml
with a 12 mg capsule.
DR.
KATZ: But this is a 24-hour slide.
DR.
HADDOX: This is steady state. This is steady state and I am going to go
back to the single dose to answer the question.
DR.
SHAFER: Let's go back to the single dose
if it is the same dose.
DR.
HADDOX: The single dose was actually
twice as high I believe.
[Slide]
This
is 24 mg and there is the 2 ng/ml.
DR.
SHAFER: So it is approximately doubling.
DR.
GOLDENHEIM: Paul Goldenheim, Purdue
Pharma. I think the answer to your
question is it is a little bit less but we will get the precise answer for you,
but steady state is achieved after two to three doses.
DR.
SHAFER: I have two other questions,
quickly. One is, the question was posed
yesterday to what extent is theft and criminal activity versus diversion from
patient activity responsible for the misuse of drugs and diversion to addicts,
and has your RADARS system been able to give us more information? We did not learn an answer yesterday when I
posed that question. Have you learned
anything from your RADARS system?
DR.
HADDOX: Well, certainly, the diversion
study is showing what the police are intercepting either in undercover buys or
busts. So, that is some idea of what is
on the street. It does not tell us
necessarily how it gets to the street.
There are people who are feigning to be patients, who are scamming
physicians. There are people who just
take the easy way; don't have to worry about learning new symptoms to fake or
getting fake medical records, they just go in with a gun or, you know, roll the
place at night. No one is quite sure
that the DEA does collect that theft and loss data and does categorize it, and
I believe Dr. Willis made some reference to that in her presentation yesterday
but those data reside at the DEA.
Even
so, that only gives you one piece of the question that you asked. That might give you a sense of what is from
theft and loss, and that sort of thing, but it doesn't say what the doctor
shopper, who in fact is not a patient, is getting on the street, or
particularly,, the bad doctor who is indiscriminate and doesn't really care who
they are writing prescriptions for.
DR.
KATZ: Dr. Schnoll, do you have a
follow-up?
DR.
SCHNOLL: Yes, we don't have at this
point specific information to directly answer that question. Most of the abusers get the drug from the
street. I think your question is how
does it get to the street.
DR.
SHAFER: Exactly.
DR.
SCHNOLL: That is something we are trying
to investigate. There are many sources
and, hopefully, as the RADARS system matures we will be able to provide that
answer but I don't think anyone knows specifically where all the drug is coming
from that gets to the street.
DR.
SHAFER: Do we even know if it is 1:10
versus 10:1?
DR.
SCHNOLL: No.
DR.
KATZ: Can you, Dr. Shafer, tell us why
you think that is important in terms of developing a rational risk management
program?
DR.
SHAFER: Sure, because part of the
purpose of the risk management program is the concern about drying up the
supply of drug to addicts. If that
supply is entirely coming from criminal activity and is not coming from
doctor/patient activity, or even if 98 percent of it is coming from criminal
activity, not doctor/patient activity, that means the ability of these surveillance
programs to impact that is going to be almost zero.
DR.
KATZ: Maybe it would be helpful to hear
more information on what specific elements of the RADARS program are designed
to yield an answer to that question.
DR.
SCHNOLL: Certainly the drug diversion
part of the program is trying to do that, but also as we do our field
investigations the field researchers go into an area and, if possible, try to
interview users, abusers in the area to get information about the source of
their drug. They also check with other
people, local police, people in treatment programs to get that
information. As of this time, we don't
have sufficient data to put together the types of ratios you would like and,
hopefully, we will be able to get that in the future.
DR.
SHAFER: How many abusers say I actually
got this by scamming my doctor?
DR.
SCHNOLL: Not many.
DR.
SHAFER: Any?
DR.
SCHNOLL: Yes, some do. Some do but it isn't that many. When we ask the question, as I mentioned,
what they say is, "I got it on the street." How did the drug get to the street? I don't know.
DR.
KATZ: As I indicated yesterday, there
are many issues that we don't have answers on and perhaps one of the things we
could accomplish is not so much to give answers in the absence of data but at
least to indicate what sorts of data are likely to lead to the right
answers. Is that the sort of data that,
in your view, would at some point in time, when it becomes available, give you
the answers that you need?
DR.
SHAFER: Absolutely. Not only do drugs have risk/benefit ratios
but programs, like surveillance programs, have, you know, cost/benefit
ratios. And, without knowing that
information, it is hard to assess whether the program is doing anything,
whether it is really worthwhile.
One
other quick question, can you give me any examples from your RADARS program of
how you have changed the marketing or promotion of OxyContin based upon the
feedback that you got from the program?
DR.
SHAFER: Well, one of the things we would
do, we would gather information, say, about someone in an area who was
inappropriately prescribing and needed more education. We would bring more education to that person
to try to bring them up to date on proper prescribing. In fact, we have one instance where a
physician was prescribing the drug inappropriately. We had some targeted education with that
physician and he realized that there were a number of people in his practice
who were trying to scam him and actually reduced the number of people to whom
he was prescribing opioids by about 20 percent.
So, there was a very effective outcome in that.
DR.
KATZ: Dr. Cicero?
DR.
CICERO: Yes, I am Ted Cicero, consultant
for the company. I run the Key Informant
study and I am also the custodian of all the central databases at Washington
University. I think what your question
was is are we going to be able to--and I think if we can show that map again
from Dr. Schnoll--
[Slide]
--are
we going to be able to look in an area where we are getting reports of abuse,
where is that coming from and also reports of diversion in those areas. You will see a lot of overlapping areas. We have identified right now at a very
preliminary level about eight areas where we are seeing both diversion and high
rates of abuse occurring. What we need
to be doing at this juncture, and we are in the process of doing it as you see
with the map you are seeing here--we have many areas where there is extensive
overlap of systems, the poison control; we have also the diversion sites; we
have the Key Informant Network.
For
instance, I can speak to St. Louis, that is where my residence is, and we are
getting reports both of abuse and diversion.
Looking into this, it appears that the two are very closely associated. Lots of the abuse is coming off the street
and appears to have been diverted in a criminal sort of way.
Now,
the question you are asking that we really can't answer is what percent of the
street drug is coming from theft or coming from a physician. We don't really have a good enough feel for
that now but the important thing I want to leave you with is that we have the
power to be able to do it. I think by
having these overlapping systems, the natural connection for us at this point
is to say, okay, we have diversion in an area.
Let's go in there and find out where that was being diverted to. Is it being shipped out of state? Is it at a local level? And the abusers themselves who say they got
it off the street, did they in fact get it from that source? My hunch based on preliminary data is that
there is going to be a very strong association between theft of a drug such as
this and what actually appears on the street.
DR.
KATZ: Laura Nagel, would you care to add
to that question?
MS.
NAGEL: Thank you. We share your frustration in trying to
determine where out of the closed system of distribution the drugs are being
diverted. What we tried to do in
preparation for this presentation is pull our cases. The majority of them are criminal cases. What Dr. Willis said was that in 60 percent
of our criminal cases the source of diversion was a physician or a
pharmacist. The other 40 percent were
drug thefts, doctor shoppers, people like that.
We separated out the doctor shoppers because we perceive that that is a
physician who is unwitting, that was duped and, in fact, wasn't necessarily
criminally liable.
So,
we feel very strongly that although there are thefts, that if we can educate
the physicians, if we can reach them whether it is in labeling, whether it is
in some sort of restricted manner, if we can reach the practitioners and
educate them on the respect for the drug and the appropriateness for
prescribing for the right patients at the right time, the right people will get
the drug. But we perceive from our
investigations that the physicians are a large, large percentage of our point
of diversion whether unwitting or criminal.
Therefore, we feel very strongly and support the committee's efforts to
reach them because we have to do everything we can and this is a huge part of
the problem for us.
DR.
KATZ: Can I just ask a little bit about
that? Do you have a feel for what
proportion of the diversion that comes from the physician as a source is
unwitting versus criminal?
MS.
NAGEL: No, I would be guessing but we
tried to do that when we broke out doctor shoppers. We didn't necessarily identify those
physicians in the category we call criminal.
If we perceived that a good doctor shopper duped them, well, education
is going to help that but we didn't feel it was criminal so we dropped them in
the lower 40 percent. But we still had
60 percent. Now, that is our cases; that
is not the universe but it is the best data I can offer you, but 60 percent of
our cases were criminal for physicians and/or pharmacists.
DR.
KATZ: Thank you. Dr. Baxter you are next.
DR.
BAXTER: This is very excellent. I would like to commend you first on the
presentation. It is very excellent that
my opportunity to speak comes right now because it seems that the key step in
risk management is the education of the physicians. In fact, the RADARS system itself is
potentially going to be very excellent.
But
getting back to the point that Dr. Crawford made and some of my other
colleagues, it is very important, once again, as you cited, that the
appropriate patient is selected. Patient
selection is going to be probably key in terms of managing the risk not only
for Palladone but for OxyContin as well.
It
also goes back to what we previously discussed about the importance of
assessing the risk of abuse because those individuals who are at high risk for
abuse are probably not appropriate for selection unless there are certain
precautions in place. I would wonder if
it would be possible to add into that boxed warning that patients with high
risk for abuse require additional monitoring.
Now, what the additional monitoring is, that can be debated but I think
that perhaps by adding that into the boxed warning that would cause physicians
who are prescribing to at least become aware that there are other considerations
when you are prescribing this medication and other opiates to high risk
patients.
DR.
KATZ: Dr. Haddox, do you care to comment
on that?
DR.
HADDOX: I am just trying to get back to
the boxed warning here. Slide 30, 31 and
32.
[Slide]
I
think that this may partially address your concern, the statement there is
where we make it a point, with the agency's agreement, that this should be in
the boxed warning. Now, if there are
other things the agency wants to consider we are certainly going to interact
with them in that regard but, to my reading, this addresses your point. Maybe I am not hearing it exactly right but
it seems to me that it sets a fairly high cautionary note early on in the
package insert, in the ads, and so forth, that this does have abuse potential
and that this should be considered when prescribing or dispensing. I would assume then that those sorts of
monitoring would be part of the consideration.
DR.
BAXTER: I wouldn't assume that. I think that if it is not said, then it hasn't
been considered. So, to go a step
further, I think that it would probably be very helpful in helping prescribing
physicians, especially those primary care individuals who are not familiar with
dealing with patients who have diseases of addiction. It will alert them that they need to first
investigate if a person does--at least ask the question because if you don't
ask the question, you know, what the heck.
DR.
HADDOX: Let me respond in two ways to
that, sir. I think now I have a better
understanding of what you are talking about.
We have a number of educational materials in different formats that
strike at exactly that point of how to do an interview looking for risk factors
for abuse or addiction. We have it in
different ways so that a physician will get the message at different times
depending on the materials to which they are exposed. As far as changing the label, we will of
course be happy to discuss it with the agency.
DR.
BAXTER: Sure.
DR.
KATZ: Dr. Maxwell?
DR.
MAXWELL: A couple of things. There was a question about trying to find out
where drugs come from on the street and, unless I am mistaken, the instrument
that is given to the field interviewers, the last one I got, doesn't ask the
question of where they got it. There is
no question like that. Secondly--
DR.
KATZ: Actually, maybe it would be better
just to take one piece at a time.
DR.
MAXWELL: Okay, but that is not a
question; it is just a clarification.
DR.
HADDOX: May I make a clarification as
well? That is not the entire contact
that the field researcher has. That is
sort of getting started, the beginning of the structured interview. The goal was to allow that person to go in. Depending on what we are looking at, those
questions are likely going to be asked.
Okay? So, the document that you
have in your briefing document is sort of the beginning.
DR.
MAXWELL: No, no, starting in June a year
ago I was asked to be one of the field researchers--
DR.
HADDOX: Oh, I am sorry, when we say
field researcher we mean the people that we have hired to go out to investigate
signals. You mean you were asked to be a
key informant perhaps?
DR.
MAXWELL: Yes. Let me also clarify that the only zip code
data that is collected from the key informants, from what I can tell, is the
zip code where I live. In other words,
if I sent in data from Ft. Worth it would not be reflected in the graphs by zip
code.
DR.
HADDOX: We are aware of that and we are
endeavoring to correct that right now by asking the key informants who are at
treatment centers what zip codes does 85 percent of your clientele come from so
we can try to extrapolate--
DR.
MAXWELL: Okay, well, that was not in the
June format. I wasn't going to get into
that until the question came up.
However, one thing I would like to ask is yesterday we saw the DENS
treatment data which was unable for most states to break out OxyContin, and it
showed that in the past users of OxyContin stayed out on the street for about
ten years from your first use until admission to treatment, but in the last
couple of years that has telescoped down to four years. Since you have the DENS data which does
specifically ask about OxyContin in terms of our questions about the abuse
liability and dependence, the question is are people becoming more addicted
quicker with OxyContin as compared to other drugs? I would very much like to see the DENS data
run looking at the lag on OxyContin as compared to other.
DR,
SCHNOLL: I don't have those specific
data right now. We could ask Dr.
McLellan to run that information for us but I don't have the precise
information.
DR.
MAXWELL: Well, I realize that but it
might be interesting.
DR.
SCHNOLL: Yes. Yes, that might be something we could do.
DR.
MAXWELL: Then, lastly, before we go
forward with approving another drug I certainly would like to see more in-depth
data. We have seen the presentation of
what RADARS is going to do but I would really like to see data showing us all
the data that has been collected, what is being collected, what is being done,
how well the system is working so that we would feel more confident that when
we then move into another drug the data are there and we know the system works.
DR.
SCHNOLL: We only had an hour this
morning to present. We have extensive
data on all of the drugs and just didn't have time, and what we selected were
just examples to show you what we can do with the data system. I understand your request but there just
wasn't the time to do that.
DR.
KATZ: I think one take-home message that
I want to make sure is left is that it seems like it is important for the
surveillance system to be able, at the end of the day, to distinguish what
proportion of street abused drugs come from the prescribing relationship versus
coming from diverted sources. So, it
sounds like people are recommending that at the end of the day we will be
comfortable that the system will be able to accomplish that.
We
are half an hour behind schedule and it looks like I have about 12 people still
with questions and I have my own questions.
So, what I think I will need to do is take one more question and then we
will have to go on to our next presentation, and Dr. Saini, you are next.
DR.
SAINI: We heard very good things about
risk management but I did not hear anything from the pharmaceutical company
regarding the NASPER program. Do you
have any comments regarding that, please?
DR.
HADDOX: For those who are not familiar,
Dr. Saini is referring to a Bill that is in Congress now that would make a
federal prescription monitoring program that would be modeled on the CASPER
program in Kentucky, which is an electronic program.
Purdue
is in favor of well-designed electronic, non-barrier prescription
programs. In fact, we have supported
those in a number of states. While we
share the intent of the sponsors for the NASPER program, I have my own--and I
have discussed with other people both in and outside of
government--reservations about if it will be too unwieldy to be useful. There are a number of issues. It is very complex, as you are no doubt
aware. But I think that prescription
monitoring programs right now are being done on a state level. They have been shown to be effective and I
think that we will have to see where NASPER goes but I have some questions and
other people have raised other questions about is it just too big a data set to
manage appropriately.
DR.
KATZ: I am going to take the privilege
of asking one more question before we stop.
We have heard from many people on the committee, and in terms of some of
our lectures yesterday about the importance of monitoring the target population
that we are prescribing these medications to for the development of negative
consequences, other opioid use, including addiction. So, my question is what aspect of the risk
management program that we are hearing about monitors our patients for those
risks, and how is that data captured, analyzed, what are the outcome measures,
etc?
DR.
HADDOX: Well, one of the key elements
there is the adverse event reporting system where abuse and addiction are by
definition serious adverse events. We
monitor that on a regular basis. But
that is a passive system, as was pointed out earlier. As part of our education, we believe and
certainly our numbers would suggest that with the education we put forth with
practitioners we are making that perhaps a little less spontaneous reporting
system and that we are sort of heightening their sensitivities. So, certainly if you look at the numbers of
cases that we have gotten in, we are getting more of that information and Dr.
Schnoll has some comments.
DR.
SCHNOLL: Yes, we also have a number of
key informants and physicians who specialize in pain management and so we will
be collecting information from them regarding what they are seeing in terms of
the development of addiction in their own patients.
DR.
KATZ: So, is it fair to say then that
there is no prospective systematic means in this surveillance system for
monitoring patients for the development of any of these complications?
DR.
HADDOX: I am sorry, I didn't capture
that.
DR.
KATZ: I was just making sure I
understood that. It sounds like the
answer is that there is no part of the system that prospectively and
systematically tried to get at the proportion of patients prescribed Palladone
or any other opioid who develop any of these negative consequences.
DR.
HADDOX: Well, again in the interest of
time, we do have a patient registry study with OxyContin that is an open-label
extension study of a number of our trials.
We are finding that the rates of aberrant drug taking behaviors or
indicators of abuse or addiction are very low in that population, the intended
population.
DR.
KATZ: Thank you. We need to move on to our next presentation.
DR.
APFEL: We forgot to respond to an
earlier question about the pharmacokinetics of Palladone. We have checked back in the data and, as we
suggested before, the accumulation of Palladone is very small. It appears to be less than 20 percent
accumulation.
DR.
KATZ: Thank you. Well, let me again thank the sponsor for all
the trouble they have gone to in putting together this information for us. We do appreciate all the effort that has gone
not only into the program itself but also into the presentation this morning. So, again, I appreciate your time and
efforts. Now we need to move on to our
next presentation and I would like to introduce Dr. Silvia Calderon, whom I
have been keeping on hold for half an hour now, who is an interdisciplinary
scientist.
Well,
it has been suggested that I call a break and I can never say no to that type
of suggestion so, good, let's a 15-minute break and we will begin then.
[Brief
recess.]
DR.
KATZ: Hello, again. Just to bring people up to date on what we
are doing schedulingwise, we will have Dr. Calderone's presentation now. We will go straight through Dr. Kreek's
presentation, then straight through to Dr. Hertz's presentation which will be
briefer than we originally thought. Then
we will be going straight through to the Open Public Hearing. There are a number of Open Public Hearing
speakers, so, to make sure that we don't have any delays, I would request that
anybody signed up for the open public speaking make their way up to this--there
is a row up in front towards my left reserved for Open Public Hearing speakers.
So,
in the near future, make your way up there so we don't need to hunt you down.
Now,
we will turn to Dr. Calderone from the FDA Controlled Substance staff who will
speak with us about the FDA's perspective on the abuse liability of
hydromorphone extended-release tablets.
Abuse Liability of Hydromorphone
Extended-Release Tablets
DR.
CALDERONE: Thank you very much.
[Slide.]
I
will try to cover the abuse liability of hydromorphone extended-release
capsules.
[Slide.]
Hydromorphone
formulations have been marketed in the United States for many years as
immediate-release tablets known as Dilaudid 2, 4, 8 milligrams, injectables,
different concentrations 1, 2, 4, 10 milligrams per ml or a solution 5
milligrams per 5 ml and 3-milligram suppositories. Extended-release formulations are currently
marketed in the United Kingdom and Canada to be administered once or twice a
day.
Palladone
represents a new extended-release formulation under the FDA review which is
under review by the FDA.
[Slide.]
The
proposed strengths of Palladone are 12 milligrams, 16 milligrams, 24 and
32 milligrams per capsules. This new
formulation is being proposed for the use only in opioid-tolerant patients and
its proposed indication is for the management of chronic moderate-to-severe
pain in patients requiring continuous around-the-clock opioid analgesia for an
extended period of time.
Palladone
capsules will release the contained hydromorphone over a 24-hour period and,
therefore, are to be administered once per day.
[Slide.]
As
it was presented to you yesterday, hydromorphone is a Schedule II substance and
shares the same schedule with other opioids such as oxycodone, morphine,
fentanyl. The meaning of Schedule II;
drugs in this schedule have a high abuse potential. They have the highest level of control for an
approved drug and, in terms of regulatory requirement, prescriber and dispenser
registration, separate record keeping by dispenser, distribution order forms,
no refills, manufacturing security and quotas, import and export permits.
Note
that the CSA classifies substances by their abuse potential, dependence on by
medical utility. We also know, note
please, that the abuse potential, the actual abuse of a drug, goes beyond the
abuse potential. There are several
factors that contribute to the actual abuse of the drug.
[Slide.]
That
is why, when we use the term "abuse liability," we refer to the abuse
potential of a drug, meaning pharmacological properties of the drug, and we
incorporate, we take under consideration, a social and public-health factor.
Under
the social, we incorporate the human sometimes extremely difficult to predict
factor. This equation also includes the
use of synthesis, the availability of the drug, includes what is known about
the drug, the information available of the drug. So it goes beyond the pharmacological
properties. It also includes the
pharmacokinetics, the chemistry, self-administration, drug-discrimination
studies, but goes beyond that.
So,
therefore, abuse liability captures other factors and puts abuse potential into
a social and public context.
I
want to also mention that usually sometimes these terms are used
interchangeably.
[Slide.]
It
is well known that mu opiate agonists produce diverse effects such as
respiratory depression, analgesia, miosis, drowsiness and also they induce
changes in mood including euphoria and liking.
Hydromorphone, oxycodone, morphine, all are mu opioid agonists. They all share the same type of properties
but they exhibit different relative analgesic and subjective effect potencies.
When
analgesia, miosis and respiratory depression are measured, oral hydromorphone
is approximately four times more potent than oral oxycodone and morphine
whereas intravenous hydromorphone is six to seven times more potent than
morphine.
It
has been also shown that when euphoria and reinforcing effects of oral and
intravenous hydromorphone were evaluated, hydromorphone was ten times as potent
as morphine in drug-abusing subjects and in normal volunteers. Therefore, based upon these numbers, 10
milligrams or oral hydromorphone will produce comparable analgesia effects to
40 milligram of oxycodone or morphine.
On
the other hand, the same 10 milligrams of hydromorphone will elicit an
equivalent euphoria to 100 milligrams of morphine. It is also known
another factor we consider in the evaluation of abuse liability is what is
known about the history and abuse of the drug.
[Slide.]
Hydromorphone
has a documented history of abuse in the United States dating back to the 1970s
and it has been subject to the DEA Task Force attention. Hydromorphone was historically the drug of
choice among opioid abusers who often administered the drug intravenously after
crushing and dissolving the 4-milligram tablet.
Also, DEA reported that the 4-milligram Dilaudid tablet street value
averaged $40 and that Dilaudid continued to be diverted and abused.
In
the next two slides, I will highlight some of the findings of the Drug Abuse
Warning Network Medical Examiners component.
Yesterday, you have heard about one of the other databases reporting in
DAWN. That is the emergency
department. But I will be talking about
the medical examiner's component.
Also,
I will present to you rates, drug-abuse rates, per prescriptions dispensed and
finally I will discuss the limitations that apply when calculating those
rates. You will see there are many.
[Slide.]
The
DAWN Medical Examiner's database reporting for the '99-2001 period 132
hydromorphone-related deaths and 1,272 oxycodone-related deaths for the same
period of time. Adjusting these numbers
by the total number of retail prescriptions, the death rates expressed as
number of deaths per 100,000 prescriptions are 7.5 deaths per 100,000
prescription for hydromorphone, 1.8 when considering the whole oxycodone market
included single product and combination products.
When
recalculating that rate, if we only include in the denominator oxycodone
single-entity products, that rate changes to 6.1.
[Slide.]
These
rates should be, or these ratios should be, considered crude estimates. We know that the Medical Examiner deaths do
not represent national estimates and we know that DAWN only captures 128
jurisdictions out of 3,000 jurisdictions in the whole country.
We
also know that the DAWN Medical Examiner Report may include multiple drug
mentions and the cost should not be attributed to any of the drugs my
itself. We also know that DAWN really
includes brand names.
Talking
about the limitations regarding the denominator, we know that sales data
represents the whole U.S. market. We
also know that the denominators include all formulations of the drug. Although far from perfect, the calculation of
these crude rates is relied upon in the field of drug-abuse epidemiology and
they have been used to put these numbers into a context.
Having
described all the limitations of the calculation, we might say that the
difference in the rates might reflect hydromorphone's high potency. Maybe they reflect a different pattern of
abuse or maybe the reports have been captured in different reporting areas.
[Slide.]
Based
upon the data reviewed, hydromorphone appears to have higher abuse liability
than other Schedule II opioids.
When compared to immediate-release hydromorphone products currently
available, due to high concentration of hydromorphone in the formulation,
Palladone has higher potential risks of misuse and overdose than might result
in death.
Also,
Palladone poses significant risk of overdose in non-opioid-tolerant patients or
if Palladone is misused and abused.
[Slide.]
So,
in conclusion, risk-management programs should be designed to address the risks
associated with this high-dose opioid analgesia drug product and, as an
example, Palladone.
Thank
you very much.
DR.
KATZ: Why don't you stay up there, Dr.
Calderone. Are there any questions from
the table?
Dr.
Skipper first and then Dr. Shafer.
DR.
SKIPPER: Thanks, Dr. Calderone. Do you, then, disagree with what Dr. Haddox
said earlier that human and animal-abuse liability for hydromorphone was
typically--is morphinelike?
DR.
CALDERONE: I think we are confusing two
terms. I totally agree that the
subjective profiles of the drug are the same.
They both are perceived different.
We have higher euphoria, higher liking with hydromorphone and, in drug
abusers, they would rather go for hydromorphone than for morphine in the same
way that hydromorphone is perceived differently than codeine. They will actually see a differentiation.
I
think that this profile is the same but there are differences among the mu
opioid full agonists.
DR.
SKIPPER: So the abuse liability is
higher for hydromorphone?
DR.
CALDERONE: If we consider the human
factor that is sometimes so difficult to predict because we cannot control, the
abuse liability is higher.
DR.
SKIPPER: Thank you.
DR.
KATZ: Dr. Shafer.
DR.
SHAFER: A couple of things. I think that you have cherry-picked the data
to make your presentation. If you take a
look at various estimates of analgesic potency, relative analgesic potency, for
hydromorphone and morphine, the Canadian package insert gives 7 to 11, based
upon acute-pain studies.
Hill
and Zackney cite a figure of seven- to eight-fold difference in analgesia
potency. Maher and Forest, 1975, give
8.6. Goodman and Gillman list 7.7. The only study that is approximately 4, which
you cite, is the study by Dunbar of 1996.
Similarly,
if you look on the other side of the equation which is the subjective effects
of the drugs, Jasinski actually gives a figure of 9. But if you look at the standard errors on
that, it ranges from 0 to 20, so it is not an exact number. I mean, there is quite a broad variation
there.
On
the scale of subjects liking, the particular thing about what do subjects taste
when they get the drug, he actually gives it a 6.8 which puts it right in the
middle of the relative potency for analgesia.
If you look at the scales that Jasinski has used and the maximum effect
in terms of subjects liking, they are indistinguishable for morphine and for
hydromorphone.
Hill
and Zackney give a figure of 10, which is the figure you cited. But, again, their standard errors on that
range from 6 to 20. So it is not clear
from looking at the data that were provided to us that it supports the
conclusion that you have drawn.
DR.
CALDERONE: Hill and Zackney confirm, or
they reported, ratio in terms--when analgesia is measured, they compared 7 to
1. The equal analgesic dose they use is
7 or, I believe that they have gone to 7.7 and their calculations were 7.7.
In
terms of Hill and Zackney, they also confirm Jasinski numbers. We have variability in terms of the
scale. That is something that we face
and it is part of the design and the methodology for these types of
clinical-abuse liability. But I feel
very confident we can report it as a ratio but I feel confident that the euphoria
and subjective effects induced by hydromorphone, the rate is higher than equal doses.
So
an equal analgesia dose is the euphoria and the liking is higher.
DR.
SHAFER: All I will say is that the data
that we were provided, the numbers don't line up.
DR.
CALDERONE: If you read the last
conclusion from the Zackney paper--for the Hill and Zackney paper--he confirms
a rate of 9 to 10.
DR.
SHAFER: I will read the conclusion if
you want, but his actual words are, "slightly higher," which is a
little bit different than how it is being represented.
DR.
KATZ: Dr. Aronson.
DR.
ARONSON: I want to pick up on a point of
your discussion. I think it is a segue
from the question that was just asked prior.
I appreciate your conclusions that this is a drug of choice by
addicts. I understand the differences of
those conclusions being drawn. But one
of the comments that was made in this morning's series of discussions that
continues to resonate in my mind was the estimation that there is about 5
percent of patients who have pain that will become addicts.
What
is your opinion? Is there data to
suggest that the likelihood of that population, that specific population, not
the addict population but the patient with pain who could become an addict--is
that chance greater with this drug in your opinion and is there data to support
that?
DR.
CALDERONE: I don't we don't have data to
support the actual--to support iatrogenic addiction. What I think, it will be an actual
estimate. I think that the percentage is
very dependent on the paper you read. I
know that those in Fishman reported, like, the incidence of the addiction in
patients could go even from 5 and I believe it is up to 15 percent.
So
your question is the hydromorphone--I would say that hydromorphone is a very
potent and positive reinforcing drug. I
think that we don't have a study to support that it will induce--the rates of
addiction will be higher with this drug.
DR.
KATZ: That is a research area of mine so
I can contribute, I think. In terms of
the question of what is the incidence of new cases of addiction in patients who
were not previously addicted resulting from the therapeutic exposure to opioids
for the treatment of chronic pain, the answer is that there are no studies that
address that issue. It is not that there
are conflicting studies. It is that
there are no studies.
The
same is true for patients with risk factors for addiction. There are no studies that address that issue.
Dr.
Skipper?
DR.
SKIPPER: I just wanted to ask one follow
up. Have we done anything to look at
street value, I mean comparative, because it seems like I have read that
hydromorphone has significantly higher street value than--
DR.
CALDERONE: Actually, we don't do those
type of studies. The information I
presented was provided by the DEA but I really don't know if the sponsor and
the RADARS data is collecting any type of information like that. I don't know.
DR.
KATZ: Would the sponsor care to respond
to--
DR.
CALDERONE: The sponsor might have some
other information than what we have.
DR.
CICERO: I am Ted Cicero, again, from
Washington University. Yeah; we do. I think, at least for OxyContin, the street
value is about $1.00 a milligram as it goes up.
The hydromorphone, itself, is about $40 a tablet, as best we can tell.
There
was also, I think, the question about potency.
I think that was raised and I think one of the questions came up and if
I can, I would just like to interject at that point. There is no data. There is absolutely no data to support the
assumption that compounds with high affinity for the mu opiate receptor are
intrinsically any different in their abuse liability.
I
think what is getting confused here is that potency is a very different issue
in terms of efficacy than it is in terms of producing abuse liability. If you look at the data, all the data in
humans and animals, if it has affinity for the mu receptor, it is guaranteed to
have reinforcing effects and have a potential for abuse liability. Intrinsically that is a feature of all
compounds that have an affinity for the mu agonist.
The
fact that one compound requires a microgram where another compound requires a
milligram to produce the same effect is irrelevant. This is an important point because you are
suggesting that a given compound, like hydromorphone, has more intrinsic abuse
potential than another compound such as fentanyl. That is simply not correct and that is based
on many other factors that enter into it.
DR.
KATZ: Thanks. Just to return to the program.
DR.
CALDERONE: I really want to go back to
that question. I really disagree.
DR.
KATZ: Go ahead. Dr. Cicero, you can go ahead and sit back
down. Thanks for your input.
DR.
CALDERONE: I really disagree with that
statement. It believe that abuse
liability is more than receptor occupancy, more than binding. There is a human component into the abuse
liability. It is true, like, Goodman and
Gillman even cites the abusers do not distinguish between heroin and
hydromorphone and they do distinguish between heroin and any other opioids.
If
you have an abuser, will go for the hydromorphone, will not go for the
codeine. So, although this is
independent of the potency and the receptor occupancy, we know that abusers
distinguish between opioids. That is why
we try to incorporate the human component into the abuse-liability calculation.
DR.
SKIPPER: Would it not be--I am just
following up my question.
DR.
KATZ: If you could just, next time,
indicate that and I would be happy to recognize you.
DR.
SKIPPER: Okay. I thought I was still recognized. But, anyway--
DR.
KATZ: You weren't.
DR.
SKIPPER: Okay. My light was still on.
DR.
KATZ: You forgot to turn it off.
DR.
SKIPPER: Would it not be valuable to do
some survey to see, at the street level, how addicts value this because
wouldn't that be where the rubber meets the road, to take into effect the human
component and is there any plan to do that?
DR.
CALDERONE: I don't know of any plan to
do that, but I think that the study should be designed carefully. We need to think about--the details of the
study should be really clear. But it
will be extremely valuable to have that information.
DR.
KATZ: Just to respond. There was a study published by Daniel
Burkhoff a number of years ago who did go into a prison to patients
incarcerated for opioid abuse and asked them to rate which ones they liked most
to least. I forget the order, but
hydromorphone was near the top of that list.
Dr.
Skipper and then Dr. Shafer and then Dr. Cush.
Dr. Shafer?
DR.
SHAFER: Let me mention that the subject
on the table here is a pharmacokinetically modified form of hydromorphone. That is very relevant because the one place
where these drugs are distinguished is the rate of onset. Heroin has a very fast onset. There it is really the rate of crossing the
blood-brain barrier.
Hydromorphone
has an exceedingly fast rate of crossing the blood-brain barrier and I am not
surprised to know that subjects find the experiences very similar with I.V.
dosing of the two.
With
an oral form which is intended to actually--and, as you saw from the graph
where the levels in the plasma rise very slowly, that pharmacokinetic
difference between the two I.V. pushes of the drugs, or let me say the
pharmacokinetic similarity in terms of the brain concentrations following I.V.
push are virtually irrelevant, so it is not clear how extrapolatable those data
are.
DR.
KATZ: I think, to summarize, it is clear
that hydromorphone, by any form, has a high abuse liability.
Dr.
Cush?
DR.
CUSH: I don't have questions.
DR.
KATZ: Are there any other questions for
Dr. Calderone based on her presentation?
Thank
you very much for speaking with us. Our
next speaker will be Dr. Mary Jeanne Kreek, whom I am delighted to
introduce. She is a professor and Head
of the Laboratory of the Biology of the Addictive Diseases at Rockefeller
University. Anyone who has got even the
most tangential interest in this area will know that Dr. Kreek has been really
a pilar of this whole field for an extended period of time and it is a
privilege for us to have her here.
Long Acting Opioids: Challenges in
Pharmacology
DR.
KREEK: Thank you very much, Dr. Katz.
[Slide.]
Thank
you all for inviting me to be here today.
I have been asked to speak today on the general topic of challenges with
long-acting opioids. What I am going to
cover today will really be a mixture of topics but really focusing on my
perspective which is addiction and the treatment of addiction.
I
really have to put up for something that is not on any slide, but I will be
addressing different kinds of problems related to long-acting versus
short-acting opiate use, some of the nuances, some of what I perceive, at
least, are the societal needs at this time.
But,
at the same time, I would like to point out one question that I think has not
been asked today and I am going to put it up front because I think it is very
central to when you are considering abuse liability, and that is who is the
abuser and who is participating in abuse.
It is an additional question to the very cogent superior questions I
heard about where is it coming from, how is it coming, how is it getting to the
abuser. Those are all very, very
important questions. But who is the
abuser is also a critical question.
I
will tell you from years of trying to answer that question, being forced to
answer that question, I have found that most of the abusers in our urban
centers are persons who actually have heroin addiction and are looking for
either sustaining their heroin addiction and/or unable to get into treatment.
I
think one thing I would like to say a priori; we must, as a society, I think,
accept addictions as diseases separate from each other in their later forms and
we must aggressively treat those addictions so we decrease the numbers of
persons at risk while--and I am primarily a scientist--we try to learn more
about the basis of addictions, who is vulnerable, what are they vulnerable for
and how can we do better primary prevention as well as early intervention.
Those
are kind of philosophical comments, but I think they need to be said and we do
need to ask who are the people misusing drugs of abuse.
[Slide.]
In
terms of major issues, I am going to start with my summary first and then I
will go into some of the specifics. Your
handout, handed out today, if you got a colored copy, is actually easier to
read. If you didn't, I'm sorry, but it
will go into things I certainly won't have time to cover.
Major
issues; I think education is critical.
How we are going to do education, how the FDA, DEA, all our wonderful
regulatory organizations and our scientists and our schools and our private
sector can all provide education. We all
have to work together to do it.
There
are some major problems very specifically related to physician use or
prescribing of long-acting opioids. They
are major problems that I think we need to think about addressing generically
as well as specifically.
One,
there has been a lack of education in recent years of classical pharmacology,
pharmacokinetics and pharmacodynamics.
That is a general statement that I think we all will concur. Look at medical students now as opposed to
five, twenty and thirty years ago.
However,
having said that, that is no excuse. It
needs to be updated and it needs to be made adequate. One of the real gaps I have found, as I have
lectured to scientists but also physician-scientists and physician groups, is
the lack of knowledge about long-acting versus short-acting opiates, mu opioid
receptor agonists.
That
is astonishing. I also find that lack of
knowledge with DEA and FDA and others in regulation as well as many other lay
people. So I think we need to worry
about the medical education. We also
have had both discovery, synthesis and development of both intrinsically
long-acting, methadone, LAAM, buprenorphin as well as formulation of
short-acting compounds into long-acting preparations.
[Slide.]
There
is also a lack of medical-school and other healthcare professional and
neuroscience education about addiction.
The specific addictions, approach to treatment, identification,
diagnosis and management. There is a
real lack of awareness of prevalence. 10
to 20 percent of all Americans have an addiction. Look around the room. There are a lot of you.
There
is lack of knowledge about genetic vulnerabilities, predictable
chronic-drug-use induced changes in the brain and environmental factors ranging
from early prenatal and perinatal problems to set and setting, peer pressure,
availability and host factors.
So
we have physicians as well as other healthcare professionals who don't know
enough about the long-acting versus short-acting mu agonists pertinent to
today's discussions and we also have physicians and healthcare professionals
that have been taught very little about addictions.
There
are medical schools that do a very good job in one or both and there are some
that do a poor job in both. The same is
true for nursing schools, for science educators at the post-graduate level. We, therefore, have problems. Inadequate knowledge; that can lead to
increased morbidity and mortality which I am also concerned about. Today is focused on abuse liability, but I
can concerned about the deaths that occur when physicians misprescribe because
of lack of knowledge.
[Slide.]
There
are also physicians with inadequate time.
The pressures of HMOs force many physicians to be close to script
writers even though they didn't plan to do and they don't want to be. The majority of problems lay in these two
realms; inadequate time, inadequate knowledge.
Some do wish for profit or are willing to, for diverse reasons, become
prescription writers; that is, the illicit practice of medicine.
I
do think this is also important. Similar
constraints of specific education and time lead to inappropriate
enforcement. I have had the great
privilege to teach many DEA field officers about long-acting versus
short-acting opioids and when it is appropriate to use which. I have to say, they have been incredible
responsive. Denise Curry and I have discussed
over the years how wonderful it would be to have even broader teaching manuals
for our enforcement people. This, of
course, is in our context of pharmacotherapy for opiate addiction.
[Slide.]
What
are the prevalences of addictions in the U.S.?
Approximately 15 million alcoholics, 2 million cocaine addicts and about
1 million heroin addicts. You see
absolutely lacking on this slide persons who are addicted to licit drugs and
broken out by type like mu agonists. We
actually don't have those data. We have
talked about it today, the need to general better data, more data.
Many
groups have tried. It has been very
difficult to do so. It needs to be done
much more thoroughly. There will be
inherent problems even if one does a better screening. For instance, we have just heard by the DAWN
network, you get a denominator that is simply compound. It cannot be finer than compound. You do not know the formulation, the route of
administration, the mode of administration, when you do such kind of detection.
This
is something that I may or may not get to today but I want to point out that
approximately 1 in 10 to 1 in 20 who self-expose to alcohol become
alcoholics. About 1 in 10 to 1 in 20
that self-expose to cocaine become cocaine addicted. About 1 in 3 to 1 in 5 that self-expose,
nonprescription, non-medically indicated, to heroin, become heroin addicted.
Again,
this becomes terribly important when one considers the question of who is
misusing or abusing a drug such as an opiate formulation. Is it someone is already addicted? Is it somebody who is a drug abuser trying a
lot of things? I think we could expect
to see very different kinds of outcomes depending on how we define the terms. Critical.
[Slide.]
What
are the factors to develop an addiction.
This is actually a very early formulation from my lab but I don't think
there is much controversy about the three major types of components. We now know that, of course, environment
plays a very important role and I have run over some of these, set and setting,
cuing, comorbidity, both psychiatric and medical, as well as peer pressure,
stress and stressors which is on some of your handouts, not on others, I am not
going to get into today.
I
would be glad to come talk another time about that, but we know that stress
and, indeed, pain is a stress, stress alters responsivity. But there is evidence to suggest in the
setting of pain, there is less of a pleasant euphoric drug effect and more of a
pleasant relief-of-pain effect.
Genetic
factors. This is sobering but many studies
have shown that 25 to 50 percent of the relative risk of developing addiction
is on a genetic basis. The studies for
alcoholism are three decades old. The
studies for other drugs of abuse are much more recent. However, there is a controversy about whether
or not there are specific genes dictating for specific addictions.
Our
own formulation is closer to that of Ming Swann at Harvard which is there will
be many polymorphisms of many genes contributing to any addiction. If one happens to have depression or anxiety
syndrome, the genes contributing to those disorders may also contribute.
But
there will also be some variants that are very specific for specific types of
drugs of abuse. I think the data, not
only epidemiology but of specific polymorphisms, is beginning now to bubble up
to support that Swann hypothesis which we also agree with.
Drug-induced
effects. This is extremely
important. The people to my left may get
nervous about it but we know that chronic exposure to drugs of abuse alter the
brain. We also know, however, that the
on/off effects of drugs of abuse alter the brain in ways that sometimes steady
state doesn't. Now the people to my left
will feel very happy because what my lab has shown is that the more one
approaches steady state, the less problems you get in altering the brain and
those very brain changes may contribute to the behaviors that we know as
self-administration and addiction. It is
a powerful statement.
[Slide.]
We
know the endogenous opioids are involved in each of the addictions. I have heard no discussion of those
today. Probably it is in more arcane
sessions but, in fact, we are always talking about the competition between the
need for more, the lack of enough endogenous opioids and, therefore, the
administration of exogenous opiates, whether it is for the relief of pain or
modulation of other systems.
[Slide.]
The
mu opioid receptor was cloned about a year after the delta receptor was cloned
by Kiefer and Evans, and Leah Yu and George Uhl. Two groups simultaneous came up with a mu
receptor which is this longest one and which has more unique amino acids,
primarily because of its length, with the other uniqueness of each of the three
receptors residing in this extracellular and intracellular space where binding
occurs and where signal transduction occurs.
This
is going to be important. I am sure this
committee has seen come and go kappa ligands and will see coming and going
delta ligands as well as mu ligands.
They have some actions in common, some differential actions and they, in
part, mimic the endogenous opioid system.
[Slide.]
It
was alluded to by Dr. Katz that I have been in the field for some years and
sometimes my former mentor, Dr. Dole, likes to refer to the fact that I started
when I was five or six, which is very complimentary. But in 1964, I had the opportunity, as a
first-year resident in internal medicine to cross 68th Street from what is now
Cornell Medical School New York Hospital to the Rockefeller University to join
a team that was then coalescing headed by Dole who recruited two women, Dr.
Neiswander, a seasoned psychiatrist working in addiction, and myself.
As
we would, like with this people that Marie sent us to see on the streets of New
York and the prisons and the detox centers, Vince and I became convinced, and
now I think there is incredible data to support it, that heroin addiction is a
disease. It is a metabolic disease of
the brain with resultant behaviors of drug hunger, drug self-administration,
despite knowledge of negative consequence to self and others.
It
is not simply a criminal behavior or due alone to any sort of personality or
other personality disorder. The elegant
studies of Weisman and Ronceville and others have shown that a wide spectrum of
psychiatric disorders may be comorbid conditions. Indeed, if you look at the flip, about 40 to
50 percent of heroin addicts have no comorbid condition.
[Slide.]
Heroin
is very short-acting in self-administration, therefore, self-administration
occurs three to six times by the heroin addict.
When they can't get heroin, they will look for another reinforcing
drug. And, yes; intravenous
hydromorphone, intravenous morphine, are high on that list.
When
they can't get a reinforcing agent, they like to get illicit methadone. It has been out there. It was called "dollies" when we
began our work, dolapinhydrochoride, and, in fact, they would all say, "If
you can get nothing else, take a dolly.
It will help you get through your withdrawal symptoms."
Now
we hear illicit use of methadone by many who are saying, "Take methadone
and self-medicate while you are waiting to get into a treatment
program." We have inadequate
treatment programs primarily, I believe, because medical education has not
taught this is the disease that must be addressed by physicians and all the
manpower that goes with physicians, healthcare personnel, in general. I think that is extraordinarily unfortunate.
If
you look at this arrow which follows our narcotics blockade tolerance paper of
'66, you will see the what we ask after the first studies where we had found
that one could induce people into treatment with this compound, and I will come
back to that in a minute, we had to study its safety.
[Slide.]
What
were our goals in '64 for a medication to treat an addiction? I present these because I think they are
critical for treating an addiction but what we have learned, and what we had
learned by the first ten years of our work, made us begin to education pain
specialists. I think some of you may
cringe on the committee but, in fact, it was crossing the street to Memorial
that allowed us to help share what we were learning with Dr. Hood, Dr. Foley,
Dr. Portenoy, names known to many of you, about the potential efficacy of
long-acting opioids and, contrary to my medical-school education, that
tolerance develops much more slowly when you have sustained opioid level than
when you have intermittent opioid level, something now readdressed and affirmed
in animal models by many groups.
So
we wanted a long-acting opiate to prevent withdrawal symptoms, to reduce
craving and also to normalize any physiologic function disrupted by drug
use. We wanted to target treatment agent
to a specific site of action such as the receptor.
Dole,
along with Collier and Martin, and our group, the three of us at Rockefeller,
we talking about opiate receptors in '63, '64, as the work was conceptualized
and then initiated in '64. But the
receptors were not fully defined satisfactorily until '73 when Schneider,
Teranius and Simon, all three, did so within a month.
[Slide.]
We
also wanted a medication that was orally effective. Why?
To get away from the lore and the dangers, then hepatitis B, later HIV,
now C, of use of needles, sharing of needles.
We wanted a--and I think this is critical and not necessarily satisfied
in some formulations into long-acting, perhaps of long-acting, drugs a slow
onset of action, a long duration of action and a slow offset of action.
Now,
there are two kinds of long-acting compounds, but, at that time, we were
looking for one with intrinsic long-acting properties.
[Slide.]
Ray
Hood had been, as part of the U.S. government, in postwar Germany and had
brought this compound back thinking it might be good for pain management. It had never been brought to the clinic in
any of its studies in Europe. This
compound was studied by Hood at Memorial and Beecher at Harvard. I am sure some of you have read the classic
papers where they found a single dose of methadone was similar to morphine and
efficacy of about three to six hours.
But
when multiple doses of morphine were given to an opiate-naive person, both Hood
and Beecher saw respiratory depression ensue.
They knew, therefore, that methadone would not be good to give to
opiate-naive or weakly-naive persons.
They, therefore, dropped it from much more studies for pain and, in
fact, it had been used only very modestly by the Lexington group for short-term
detoxification of opiate addiction.
But
when I read that study, or the studies, from Beecher and from Hood, it became
apparent to me that, even though we had no gas chromatography, no
radioimmunoassay, we had to look and talk to patients to make our observations,
that this compound might be intrinsically long-acting and, clearly, morphine
and heroin, in its diacetyl man-made variant, are not. They are very short-acting.
[Slide.]
So
we started with low-dose methadone 10 to 20.
This is an induction which is still recommended for methadone and
buprenorphine. Start with low doses and
taper them up even when you have evaluated that a patient is tolerant, then,
going up still slowly, so that the degree of tolerance was never exceeded. We found that a person could be totally
functional behavioral with no drug craving.
[Slide.]
In
our cross-tolerance studies, we superimposed intravenous heroin, intravenous
hydromorphone, intravenous methadone and intravenous saline against the
background in two series, each four weeks long, of Latin square, double-blinded
designs. We found that 80 to 100
milligrams a day of methadone would blockage against the intravenous effects of
up to 200 milligrams of heroin.
Now,
these were important studies that have been replicated four times for
methadone, two times for buprenorphine and two times for LAAM. Cross tolerance develops. Cross tolerance is critical.
When
we introduced the concept that methadone, indeed, is superb for management in
chronic-pain patients, and parenthetically has become the major analgesia of
choice in several countries, we taught induction, stabilization, but here to
stay just over the degree of tolerance developed by an individual to be able to
achieve pain relief.
And
the groups doing that find that much lower doses sometimes in the realm of 30
to 50 mgs a day are adequate.
[Slide.]
One
can see this tiny bump clinically observed.
We found that, indeed, methadone was profoundly different; oral onset
after 30 minutes, duration of action 24 to 36 hours and withdrawal
symptoms after 24 hours. But it was not
until a few years later, about nine years later, that Chuck Interisi and I
independently developed gas chromatographic methods for measuring plasma levels
of methadone.
What
one sees after an oral dose is this modest rise, barely a doubling of the nadir
and then a steady state over the 24 hours.
The 22 to 24-hour data were not published until 2000 when Jay Pett let
us publish it as part of a PET study. It
is flat as a pancake.
When
methadone is used in divided low doses for management of pain, most of my
colleagues in pain management prefer to give it two times a day or sometimes
three to get this modest little bump. It
is not necessary to do so and we hold their hands, but patients sometimes feel
more comfortable having that bump.
Heroin
has a half-life of three minutes, its 6-acetyl metabolite, 30 minutes and about
four hours for the active monitor metabolite.
Methadone, both Interesi and I learned, in its racemic for use in
therapeutics for pain or addiction has a half-life intrinsically of 24
hours. Using stable isotope techniques
with selected ion monitoring GAMS, we learned that the active enantiomer has a
half-life of 48 hours. This is what
we find at the 22 to 24th hour after methadone dose, flat as a pancake.
[Slide.]
We
went on to ask how much occupancy of the brain is required working with
Eckelman here at the NIH and Kenner Rice, we first were able to map thirteen
major regions of the brain for mu receptors not done before this study. We have a steady-state ligand for
radionuclide as long acting as is the compound and we found that, indeed, the
pain regulation center of the thalamus has the highest amount of mu receptors
in healthy humans followed by the limbic system which we know is involved in
reward, emotion and addiction, the amygdala, the anterior cingulate as well as
the nigra-striatal system also involve in long-term memory and consolidation,
the caudate and putamen, part of the nigra striatal system.
[Slide.]
Shown
in the orange bars, as we predicted, there is less than 20 to 30 percent
occupancy by methadone during steady state when doses of 80 to 100 milligrams a
day, adequate treatment doses for many patients, are used.
[Slide.]
We know that this was a predicted result since our laboratory and others had shown that each of these functions, disrupted by the on/off effects of short-acting opiates such as heroin including