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?