The First International Conference On Heroin Maintenance: Clinical and Treatment Issues, Robert Haemmig

He was saying this in relation to methadone maintenance, and he was criticizing that this heroin prescription was not introduced in a proper way into medical practice and implicitly he said that methadone, of course, was. But if you go back into history and if you look at how this methadone maintenance was introduced, it was absolutely the same way. Methadone was not tested against any other substance. There was no randomized double blind trial.

Dr. Jerome H. Jaffe once told me that at the time when methadone was introduced, there were maintenance prescriptions going on with hydromorphone, which I think is quite an interesting substance for substitution. And they just were stopped without any trial .

Actually, I'm not one of the Swiss researchers, but I must admit, I am a true believer. So, the question is, what do I believe?

Because I'm a medical doctor, I believe in medical ethics and medical ethics are not such a special thing, that they were restricted to the actions of medical doctors. Social workers, psychologists, field workers of any kind act on the same ethical base. My work has four ethical goals and the first one is reduction of mortality and the second one reduction of morbidity. And thirdly, I have to alleviate the suffering, if the patients cannot be helped properly, and fourthly I should not damage my patients by my treatment. Normal thing in medical practice.

So I will tell you a "normal" story of a patient of mine. I will try to show you how the decisions are made in practice. My patient was born in 1967. She had experienced a divorce of her parents. Shortly after this, there was an episode of sexual abuse. Her stepfather was "playing" with her when she was 14.

So slowly, slowly, she developed alcohol abuse, at a time when she was still going to elementary school. She remembers very well the first time she had taken heroin. She was out with friends late at night and had forgotten the key. So when she came home late, she had to ring at the door. Her stepmother opened the door and just said "you're drunk again". This was the only reaction. This was a very important event for my patient, because there was no appropriate response, a thing we see very often in the history of addicts.

So of course, doing drugs in school and drinking alcohol, she was not able to have a professional formation. And then after two years of heroin, I took her in a methadone substitution.

This methadone prescription was quite frustrating for her because she never felt well. She is probably one of the patients with a short action of methadone. Her pupils were extremely wide after two or three hours after a normal dose. The more methadone she took, the worse she felt.

Because of legal restriction I could not dose her over 120 milligrams a day. In her case the symptoms of withdrawal were worse at 120mg/d than at 60mg/d.

What did she do in this situation? She helped herself with heroin and cocaine and some flunitrazepam. So in 1994, when I had the opportunity to take her into the heroin prescription, I did it, of course. She stabilized in a very short time. She was stable for such a long time that we decided in the end of '97 that she should go on detoxification, and she had planned to go into inpatient rehabilitation somewhere in Italy afterwards.

But after two months in this place in Italy, she returned to Bern. The reason for disrupting the rehabilitation was that she felt so bad. She was detoxified, but she felt depressive from morning until night, could not feel any joy, couldn't sleep at night, felt exhausted, and had a feeling of losing control of the environment. Back in Bern she relapsed, of course. She did an overdose and she prostituted herself for the first time in her life to buy some heroin. So I took her back there into the heroin prescription.

You can see, that my judgement of the patient's situation was wrong. She was doing fine on heroin prescription, but actually, there was no move. She just stabilized on a level which was not very pleasing. Mainly it was not pleasing for me, because she did not work, was dependent on social welfare. We tried to go beyond and forced her in a thing which was retrospectively very dangerous for her because it put her into the risk of high mortality.

So, when she came back to me and was saying "I'm back to illegal heroin", I had to check my ethics: do I reduce morbidity and mortality, do I alleviate the suffering and do I not damage her by the treatment? Under these aspects I had to take her back into the prescription as quick as possible.

The most important advantage of this heroin prescription is the good retention to this treatment. Because she was so compliant, she brought me to the wrong judgement to send her on to detoxification and rehabilitation, which was against the fourth point of the medical ethics and consequentially against the other three points as well.

But, according to the scientific literature, good retention does not seem to be a good thing if it is connected with a heroin prescription. The study by Richard Hartnoll and coworkers (Hartnoll et al. Arch Gen Psychiatry 37:877-84, 1980) was quoted several times today already. It was a controlled trial, the only one so far, with a rather small number of patients but actually we can draw some conclusions out of this.

They used maximum doses of 120 milligrams a day, both for heroin and methadone. After 12 months, they saw that heroin prescription had a higher retention rate, that there were more incarcerations in the methadone group and that more patients were abstinent in the methadone group, and that on the other side, more patients in the methadone group were involved in heavy street drug use.

This study was very influential because it served as an argument against heroin prescription. It was said as a conclusion, that heroin was a stabilizing drug and methadone was the drug that motivated people to change their life style. So this was used basically against heroin.

In the heroin group, they all used to some degree street heroin and actually, if you look at this study from a nowadays point of view, you must admit that the people in the heroin group were heavily underdosed. As a comparison, our patients use in average approximately 500mg of heroin per day. So if you do an inappropriate treatment concerning the dose, you have to expect that people continue to use street heroin at the same time. And even then, with this inappropriate treatment, they had this higher retention rate in the study.

A problem is that we have not exact data on the equal potency of heroin and methadone. In our Swiss trials, we had the opportunity to observe how much methadone the people need when we switched them over from controlled doses of heroin to methadone.

The following diagram shows the figures I could collect.

There is a linear correlation, and interestingly, even in high doses, you have this linear correlation. From the figures we can derive a factor that we can use to switch people from heroin to methadone. The factor is 0.28. If I multiply the daily heroin dose with 0.28, I get the appropriate daily methadone dose.

The question is why are people so afraid if we talk about heroin? Interestingly, we do not know very well how heroin works. I found quite an old study from '55, which was published in JAMA, and this study was on the effects of heroin and morphine in healthy volunteers. Studies with not addicted people or so-called post-addicts are very rare -- they are almost impossible to find. This one was on a small number of 20 people, college students.

Heroin, morphine in volunteers 13/20 consider opiates to be unpleasant 7/20 experienced euphoria: this group was characterized by: immaturity impulsiveness self-centered & emotional tendencies von Felsinger, Lasagna, Beecher. JAMA 157:1113-9, 1955 Thirteen out of 20 students found it very unpleasant to take opiates. The seven of the 20, who experienced euphoria, were characterized in the Rorschach testing by immaturity, impulsiveness and emotional tendencies, which is not the normal personality structure. I think this are quite interesting findings, because normally people think that heroin is a substance which produces immense euphoria. But people normally experience not euphoria, they experience dysphoria.

So, is heroin really special? Actually, it's not sure if heroin has effects by itself. What is clear nowadays, is that the first metabolite 6-mono-acetyl-morphine, morphine, and morphine-6-glucuronate are active metabolites of heroin (=diamorphine or diacetylmorphine). The effects we can see in patients on heroin are not produced by heroin, they are the effects from the 6-mono-acetyl-morphine, morphine, and morphine-6-glucuronate. This can be demonstrated in the diagram of the plasma profile of heroin and its metabolites.

.The green line in this diagram is the heroin. As you can see, there is a quick decline of the heroin in the plasma. At the time point of 10 minutes, the heroin level goes to zero. So if you take a plasma profile of a patient who has got 200 milligrams of pure pharmaceutical heroin, the heroin disappears within 10 minutes. And as you know, the heroin acts longer than 10 minutes. This clearly shows that heroin acts through its metabolites.

Actually, the plasma profile may not reflect the situation in the brain. It could be quite different from what you can see in the plasma, but the plasma is the compartment that is most easily accessible for us for investigations.

To know more about heroin in relation to the better-known morphine, we did a double blind study. For this we needed the equipotency of doses between intravenous morphine and heroin. If you go through the scientific literature you can find any relations for heroin to morphine from 1:2 to 1:40. Twycross, he's an English doctor who was working a lot with oral heroin, found out a relation of 1:1.5, and actually it seems to be the same relation for intravenous heroin to morphine.

So we used this relation in our study. The design of the study was double-blind with crossover. We randomized patients into 2 groups, one starting with heroin, the other one with morphine. In the middle there was a crossover to the other substance.

The interesting thing was that of the 18 patients randomized in the group starting on heroin, two drop out before the cross over to morphine. At the cross over to morphine, 13 of our remaining 16 patients dropped out. Regular termination of this study, which lasted six weeks, was obtained only in three patients.

In the group of 21 patients starting on morphine, seven dropped out before the cross over to heroin, zero patients dropped out after the crossover, so the whole remaining 14 accomplished the study.

Why did our patients drop out? Almost all of them had huge histaminic reactions on morphine. These were really dramatic at the day of the crossover from heroin to morphine. People fainted and collapsed and had itching, headaches, but all reactions passed within half an hour So we can say, there is a difference between heroin and morphine, and especially in high doses that we are using in these patients, and the difference is dramatic.

Interestingly, patients are not able to discern in any instance if they get heroin or morphine. This finding is not new. There is a newer report consistent with our data from the U.S. by Jasinski and Preston (Jasinski DR, Preston KL. Comparison of intravenously administered methadone, morphine and heroin. Drug Alcohol Depend 1986; 17: 301-10).

–Patients are able to recognize the substance better than just random, but their recognition is not 100 percent. There are patients who would take morphine for heroin.

So if you have the choice between morphine and heroin as a maintenance agent, the decision to use heroin instead of morphine is clear, and can be based on a rational, an analysis of data obtained from this double blind trial.

Let us switch to another issue. When I was young people were telling me that an addict, a morphinist, is someone who's always taking more and more drugs. Of course, I doubted on this because if this would have been true, you could calculate the date when this addict would inject his own body weight of morphine. So there must be a limit at some point.

Because all these substances like opiates and cocaine act through receptors, and the receptors are not infinite in number, there must be a natural limit of action. When all the receptors are occupied by the substance, then you will have no additional effect by additional doses of the drug, and this we call saturation. There will be no infinite raise of dose beyond this saturation point.

We know this phenomenon from our experience with methadone . All the patients on methadone stabilize on a certain dose and they do not go beyond this certain dose. We know this, but if it comes to heroin and morphine people forget all and it's like these substances would also act on the brain of the people who are not taking the substances themselves.

Interestingly, clinical evidence demonstrates that there is a negative correlation between dosage and euphoria. The more heroin you take, the less euphoria you have. This mechanism is a powerful self-regulator of the patient's dosage. Nobody will have an interest to take more and more, because it has no additional effect. And in the end, which is also our clinical observation, people have more effect if they take less.

So my patient, she was on 500 milligrams a day just before she decided to go on detox, and now, after she restarted the heroin prescription, she tries to stay on 300 milligrams a day and actually, if I want to find a positive clue to her story, she has probably more euphoric effect nowadays than she had before she went on detox. Thank you.