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effect of a narcotic and an antipyretic-analgesic given together is often significantly greater than the analgesia achieved by doubling the dose of either drug administered alone.

Furthermore, antipyretic-analgesics probably exhibit a ceiling of analgesic effect at about the usually used doses-650 to 1,000 milligrams and the usefulness of higher doses may also be limited by increased incidence of adverse effects and serious cumulative toxicity.

Increasing doses of codeine, propoxyphene and other narcotics are associated with a progressively increasing incidence and severity of gastrointestinal and central nervous system side effects and increased risk of drug dependence.

The problem of providing adequate pain relief in the face of the above noted limitations of currently available analgesics may sometimes be circumvented by combining an optimal dose of an antipyreticanalgesic with an orally effective narcotic in a modest dose which is reasonably safe and well-tolerated.

Older relevant studies for both codeine and propoxyphene combinations are cited in my 1966 review. There are a few more recent studies which appear to demonstrate a significant increase in analgesic effect produced by the addition of propoxyphene to acetaminophen.

Dr. Moertel and his associates showed a small increase in the effect of aspirin 650 milligrams produced by the addition of propoxyphene napsylate 100 milligrams, but the difference was not statistically significant.

Now I would like to briefly touch on the adverse effects of propoxyphene. There are really three types and it is important to think clearly about this issue, to keep these types of adverse effects separate in one's mind, because they have different implications in relation to drug abuse.

These three types are adverse effects seen at recommended therapeutic doses; adverse effects seen in overdose and the issue of drug dependence on propoxyphene.

In relation to adverse effects of propoxyphene at therapeutic dose levels or recommended dose levels, which is propoxyphene hydrochloride 65 milligrams or propoxyphene napsylate 100 milligrams, propoxyphene produces an extremely low level of adverse effects.

As a matter of fact, most studies are unable to demonstrate a significantly higher incidence of adverse effects with these doses of propoxyphene than with a placebo.

When large enough groups of ambulatory patients are studied to demonstrate any difference in terms of adverse effects between therapeutic doses of propoxyphene and placebo, the adverse effects consist of a very low incidence of nausea and drowsiness.

Considering the extraordinarily large use of propoxyphene products, there is extremely little in the entire literature which indicates that the drug in recommended therapeutic doses can produce any serious adverse effects, and even minor adverse effects seem to occur only infrequently.

Now, concerning the toxicity of propoxyphene in overdose: As noted above and as is amply attested to by numerous individual case reports and several epidemiologic studies; propoxyphene, like any

other narcotic, can be lethal in ovedose; although the full extent of this problem was not appreciated until relatively recent.

Back in the late 1960's we were aware of only occasional cases of overdose. I can recall that, when I reviewed the New Drug Application in 1971 for the FDA, I really could only scratch up a handful of lethal cases of propoxyphene overdose from its introduction until that time. My guess is that the very substantial increase which has appeared over the course of the last several years does not necessarily reflect a true, very substantial increase in the number of propoxyphene related deaths, but rather that dependable analytical methodologies to demonstrate propoxyphene in the bloodstream was only really developed and became available in the late 1960's and the early 1970's.

When you start looking for something with a useful tool, you begin to find it, and that may account for the discrepancies.

In regard to the dependence liability of propoxyphene, since propoxyphene is pharmacologically a narcotic, it has some ability to produce drug dependence of the narcotic type, and this has been recognized since before the drug was marketed.

Propoxyphene can produce the classic triad of psychic dependence, physical dependence and tolerance, and, in those patients who are able to tolerate high enough doses to result in substantial physical dependence, a narcotic-type abstinence syndrome has been observed on withdrawal.

"Street abuse" of the drug clearly occurs, as does dependence secondary to therapeutic use. However, in my opinion, relative to the extremely wide use of propoxyphene, the demonstrated incidence of serious deliberate abuse of the drug to experience its mood effects is not great and is certainly less than is the case with potent narcotics. Senator NELSON. May I ask a question. Dr. Beaver? Yesterday, the witnesses who testified from North Carolina and Oregon were divided on the question of whether or not intentional overdose was a serious question.

One of the witnesses felt very strongly that a good many, over half of the deaths that occurred, were not drug abusers or those who intentionally overdosed themselves, based on the study of the stomach contents and so forth. So his argument was not because it was being abused-any drug can be abused-but because people were getting overdoses unintentionally.

Dr. BEAVER. Let me clarify the point. I believe what the medical examiner from Oregon was pointing out was that he felt that many of these deaths were associated with accidental overdose as opposed to deliberate suicidal overdose. That is the distinction I think he was making. Neither of those things is the same as what I am talking about, which is the deliberate use of the drug to experience the mood effect; that is to say, drug abuse considerations.

Senator NELSON. I was only saying, if it was the Oregon witness, that it is his feeling that most of the deaths were not intentional overdosages.

Dr. BEAVER. Were not suicidal, but neither suicides nor accidents are specifically related to the use of the drug for mood effect.

Senator NELSON. I understand.

Dr. BEAVER. What I am talking about here is the degree to which people seek this drug out and take it to get "high" and that sort of thing, the same way heroin is abused. I am pointing out that that type of abuse of the drug, from what I can tell, is relatively low, and it was predicted to be low on the basis of the work that was done back in the 1950's for very particular reasons.

I digress from my testimony because it is important to explain this. Physicians are very sensitive about this. They are almost paranoid about the issue of inducing drug dependence in their patients with the narcotics they give them. So there has been a tremendous effort over the years to develop narcotics which would not have that effect, good analgesics which do not have a narcotic-type abuse liability.

Darvon was, in part, a result of this line of work. When it was tested at Lexington, it turned out it did have the narcotic-type abuse liability, but only to a very limited degree. If you gave small doses to the postaddicts they would report it as being narcotic, but they said, "It is very weak, give me more." You give a higher dose and they say, "Yes, that feels better, but give me some more." So you give a higher dose and some subjects would have convulsions. Propoxyphene has a toxicity which discourages deliberate abuse in the sense of people taking it to get "high" and, of course, the whole focus at that time was to avoid such problems.

You see, the problem that this brings along with it is that you have a drug which may be inherently more toxic when somebody takes it in overdose than conventional narcotics. So you have the two-edged sword. You are trying to make a drug that people do not like to abuse, and you do it by making the drug more toxic, but this creates certain other kinds of problems. I am trying to bring out the history of why we are in the situation we are in at the moment.

Senator BUMPERS. Dr. Beaver, you heard Dr. Adriani's response to my question about what the dangers are and he said it is the part of propoxyphene that goes to the liver and becomes nor-propoxyphene and builds up in the liver and stays in the body and cumulatively, the danger is greater than normal analgesics.

Dr. BEAVER. This is a interesting hypothesis and I will mention this further in my testimony. I would point out we know very little about nor-propoxyphene. There are only a couple of studies in the literature on the metabolite when it is given alone to animals. We know essentially nothing about what this material does when given alone to man.

Most of the Darvon overdose deaths which I have read about in reviewing the literature can very adequately be explained simply on the basis that this drug is a narcotic and produces narcotic depression and coma; produces convulsions which makes it harder to treat the overdose and the patient then dies.

The nor-propoxyphene matter is something that has recently come up and represents an interesting pharmacological lead that may, in fact, account for some of the aspects of the poisoning that we have not been able to account for. But one must make the distinction between something which is well established scientifically, in fact, and something that is just an interesting pharmacological lead.

Senator HATCH. Doctor, it is my understanding people are not dying from propoxyphene per se, but from ingesting overdoses of the drug

and the testimony has been that from 10 to 20 times the normal dose is the amount causing these deaths.

Yesterday, Dr. Moertel of the Mayo Clinic and Sidney Wolfe, a physician, indicated, if I am correct, that two capsules of Darvon were lethal.

Dr. BEAVER. That is categorically not the case.

Senator HATCH. In other words, you are totally refuting what they

say.

Dr. BEAVER. I do not believe they actually said that, but it is not the

case.

Senator HATCH. Assuming they did, why would they say something like that?

Dr. BEAVER. Did you say that?

Dr. WOLFE. I was quoting the coroner in San Francisco who said people using it on a regular basis, twice the normal dosage, not two capsules we are talking about but two capsules every 4 hours instead of one.

Senator HATCH. I am glad you were here to correct that.

With regard to those who take propoxyphene regularly in recommended dosage over many years; some people have indicated they may be dying from a drug buildup.

What does the record show with regard to that, is there a buildup potential here?

Dr. BEAVER. There is a buildup when the drug is taken repeatedly at 4-hour intervals at the recommended dose of 65 milligrams.

Senator HATCH. I see.

Dr. BEAVER. At the recommended dose of 65 milligrams there is an accumulation of both propoxyphene and nor-propoxyphene. Both of these flatten out at some level because the more there is, the more rapidly both of these things are eliminated.

You get to the point here where the amount coming in equals the amount going out, at which time you get a plateau.

For the usual recommended therapeutic dose of propoxyphene there is no evidence that when you take 65 milligrams every 4 hours indefinitely you can build up a blood level of either or both of these materials which is fatal.

Senator HATCH. As a matter of fact, at the University of Utah, Dr. Finkel indicated that the record shows millions of patients who use it in the normally prescribed manner do not suffer any serious or fatal effects at all, is that correct?

Dr. BEAVER. That is correct.

Senator HATCH. And Dr. Finkel's findings affirmed that.

Dr. BEAVER. That is correct.

Senator HATCH. Do you know of any deaths which occurred from normal, prescribed use?

Dr. BEAVER. I have not been able to identify any, but you see, often with the literature on this subject even the medical examiner is not certain of what dose was taken. When you have somebody who is dead, it is sometimes not possible to determine how much of what they took, particularly until very recently when you had methods for measuring blood levels. I found no evidence that the usual therapeutic dose of propoxyphene can result in death, and, as I pointed out, it does not

even tend to result in much in the way of subjective side effects or even serious adverse effects.

Senator HATCH. Or even a buildup which could cause death?

Dr. BEAVER. Yes. Now, the matter which I think is a reasonable question here is what happens if someone crowds the dose a bit because they are not getting enough pain relief in taking 65 milligrams every 4 hours, so they decide to take twice that-130 milligrams every 4 hours. This will accumulate to a higher plateau level and there will also be more propoxyphene in the blood.

A lot of people in fact, take double the dose and they seem to get away with it, though you get more side effects. Then the question is, if on top of that situation somebody then takes a modest overdose, but not a massive overdose, whether you now have the stage set for a lethal occurrence, and I think some of these cases that were described by the coroner in Oregon may represent that kind of a situation.

That, sir, is my educated guess from looking at the data in the literature. Somebody has already gotten up to a blood level such that even a small overdose on top of that-in other words, it no longer takes 15 to 20 capsules to kill you, which is what McBay and Hudson would say is a single lethal dose, but now a lower single overdose will kill if the person has already been taking it for a long period of time.

Senator BOSCHWITZ. If the person is taking it as prescribed, it is not a problem. Is that your conclusion?

Dr. BEAVER. Yes; that is my conclusion, and I do not know if any of the people who testified here have argued that if it is taken as prescribed it constitutes a problem.

I think the problem, as I envision it, is that propoxyphene is a drug which is very commonly available and, in overdose, quite clearly can kill.

Senator HATCH. What you seem to be saying is that overdose is drug abuse and that overuse coupled with other drugs or alcohol can kill. Dr. BEAVER. Yes.

Senator HATCH. But you do not think anybody would refute your statement that normal, prescribed use would not kill and would not be dangerous to the normal human being?

Dr. BEAVER. That is right, but you have to consider the issue as to the margin of safety and how far these two doses are away from each other in any given case. If they are close enough you can have a fairly risky situation.

It is obvious that if you have a drug which used in its appropriate way at a certain dose produces no serious side effects and it takes a hundred times that to kill you, that drug is safer than a drug which, if you only take ten times the usual therapeutic dose can kill you, because the likelihood of people dying from overdose is going to be inversely related to the size of the lethal overdose relative to the therapeutic dose they usually take.

With aspirin, it is hard to commit suicide because most adults cannot stomach enough aspirin to poison themselves.

Senator HATCH. With regard to Darvon-in the prescribed dose it is not a serious drug problem?

Dr. BEAVER. I would say that. I would like to continue my discussion briefly with the adverse effects of alternative mild analgesics