This is Part 3 of 3 of Dr. Steve Shafer's answers to MJJCommunity questions. In this third and final installment Dr. Shafer will be answering questions about Propofol, Lorazepam, Flumanezil, Insomnia and related matters.
Questions about propofol in general
MJJC: Do you feel that your testimony helped alleviate patient concerns about Propofol or are things more or less the same?
Dr. Steve Shafer: It may have helped, but only a little. On the Friday that Paul White testified I was working at the “Allen Pavilion,” a regional hospital run by Columbia University that serves a low-income area of Manhattan and the Bronx. I was caring for an elderly man who asked what drug he would get. I told him “propofol.” As usually happens, he asked if that was the drug that killed Michael Jackson. I told him that propofol didn’t kill Michael Jackson, Conrad Murray killed Michael Jackson. I also said that propofol was very safe drug. He said “I heard that doctor say that at on television, but I don’t believe him.”
I told him I was the doctor he saw on television. He thought that was hilarious: the doctor in blue scrubs, wearing a surgical hat, with a stethoscope around his neck working in this clinic for poor patients might be the “famous” doctor he saw on television. “Yea, right” was his answer. He didn’t believe me for a second. However, he was reassured by my “joke” about being the doctor he saw on television, and everything went well.
MJJC: Can a person become dependent or addicted to propofol? If yes what kind of dependency is it physical or psychological?
Dr. Steve Shafer: There is not much data about this, because propofol must be given intravenously, and it really burns, which discourages abuse. However, there have been a number of deaths of anesthesiologists and other health care personal from propofol abuse. Based on this, I am reasonably confident that it is addictive.
MJJC: Why would someone even have the idea to use Propofol as a sleep aid? If it is only to be used for surgery then why would anyone suggest giving it someone to get some sleep?
Dr. Steve Shafer: The mechanism of action of propofol is the same as drugs like Ambien that are commonly used to induce sleep. This is a reasonable research question. However, it should never be put into practiced until it has been studied in a proper research setting. After that work has been done, it should only be used with appropriate documentation and precautions.
MJJC: Are the drug companies who make Propofol looking into testing Propofol for sleep? Do you think there will be more research studies about Propofol being used for sleep?
Dr. Steve Shafer: Yes to both questions.
MJJC: What are the known effects on the nervous system & the brain of long term Propofol use?
Dr. Steve Shafer: Not a lot, because it is rarely used for long term use. I have been able to find one report of a patient who received propofol in the intensive care unit for 51 days. This is from the conclusion of the article: “To our knowledge, this report represents the first documentation of propofol use for long-term sedation in a mechanically ventilated pregnant patient and the longest duration of continuous infusion propofol published in the medical literature. Propofol was used for 51 days with no documented maternal adverse events.” (Tajchman SK, Bruno JJ. Prolonged propofol use in a critically ill pregnant patient. Ann Pharmacother. 2010;44:2018-22)
This patient was weaned from propofol over several days without adverse consequences. So administration for 2 months appears to not have long term consequences, at least based on this example, and the fact that Michael Jackson continued to function at rehearsal. However, those are just two data points. More research needs to be done if one contemplates development of propofol for long term use.
MJJC: Does one get a "restful sleep" from Propofol? We have heard experts contradict each other on this.
Dr. Steve Shafer: The contradiction reflects the state of the science. I received propofol for anesthesia about a year ago, and I have given propofol to thousands of patients. There is often a feeling of having slept well after awakening from propofol.
However, studies suggest that propofol sleep it is quite different from normal sleep, and is not “restorative” the way that normal sleep is restorative. For example, dreams are important in brain function. Patients don’t dream on propofol, except at the time of awakening. My interpretation of the data is that propofol might be OK for getting a patient off to sleep, but that maintaining a patient on propofol for sleep (as we sometimes do in intensive care units) probably is denying patients restorative sleep.
MJJC: Do you agree that Propofol should be re-classified as a controlled substance?
Dr. Steve Shafer: No. I think this will hurt patients. In emergencies we need propofol immediately, and in large quantities. I am opposed to placing obstacles in the way of doctors caring for patients, unless there is clear benefit. Conrad Murray could have still obtained propofol for Michael Jackson, because doctors can order controlled substances. Since most propofol abuse is by doctors, making it controlled won’t limit the ability of doctors to abuse it. It will just impair their ability to care for emergency patients.
This has been the subject of an issue of Anesthesia & Analgesia. Here is the cover of that issue:http://www.aaeditor.org/HWP/Covers/0710.cover.jpg.
MJJC: Do you think now the anesthesiology community will be more careful in how they promote and teach one to use Propofol?
Dr. Steve Shafer: We already take this very seriously. We are very involved in teaching the safe use of sedatives to our medical colleagues. This will continue. Perhaps they will be more receptive to the importance of safe sedation. However, nothing we can do will reach a doctor who does not put patients first.
MJJC: Do you think the medical community has learned from Michael’s death in regards over prescribing to a powerful wealthy person and wrong doing by a doctor?
Dr. Steve Shafer: Absolutely. I mentioned this above. I am aware of this because I occasionally see this in my practice. Doctors serve patients by acting as doctors. That is a message for doctors and patients alike.
MJJC: Can you explain “Propofol lollipop” a little more?
Dr. Steve Shafer: Propofol absorbed from the stomach never reaches the brain, because it is all removed by the liver. However, the blood supply to the mouth and esophagus (above the diaphragm) does not return directly to the liver. Instead, it just goes to the heart, and from there goes everywhere including the brain. So a propofol lollipop would provide propofol to the venous blood, and from there to the brain. Paul White and I discussed this at one of the breaks prior to his testimony. It is a reasonable idea, provided the dose was adequately controlled.
Should this ever become available, then I would reconsider my position on classifying propofol as a controlled substance. My current view is highly influenced by the fact that it only works when given intravenously, and that really burns!
MJJC: What does Propofol taste like?
Dr. Steve Shafer: It has the consistency of skim milk, and tastes like a very medicinal salad dressing.
MJJC: Beagle Propofol experiment done by the Defense has made PETA and MJ fans angry. We don’t expect that you have any direct information about the Beagle experiment but as the humans weren’t affected by drinking Propofol, is it safe to assume that the Beagles were unharmed as well?
Dr. Steve Shafer: I think it is very unlikely that any harm came to the beagles. There should be no effect from drinking propofol. However, I am uncomfortable that neither the experimental protocol nor the results of the experiment were presented in court. I believe that when animals or humans participate in trials, there is an ethical obligation to write up and publish the research to add to the body of knowledge. It is the increased knowledge that morally justifies the research. I wrote our human study up for publication, asked Paul White to review it, and gave it to the defense. I believe they should have done the same with their beagle study.
MJJC: We heard the theory of some of the Benzos or/and Propofol that were given to MJ by Murray can be used for people with drug addiction to help them off their addiction to other drugs such as Demerol, Is this true? Can you comment on this?
Dr. Steve Shafer: There is a technique of rapid detoxification that involves placing patients under general anesthesia for a long period of time (hours to days) and pharmacologically reversing opioids with “opioid antagonists”, drugs that chemically block the effects of Demerol and similar drugs. This is controversial, but it probably works in some patients.
Questions about Demerol
MJJC: Was the amount of Demerol Dr. Klein give to Michael normal or was it too large a dose?
Dr. Steve Shafer: I can’t answer without knowing why Demerol was given. Dr. Klein did not testify at the trial. I’m uncomfortable offering any opinion without more information.
MJJC: Does your answer change if you consider MJ’s history (burn victim) with the drug? Do you think it was excessive?
Dr. Steve Shafer: Again, I apologize, but I don’t want to render an opinion without knowing why Dr. Klein was administering Demerol. This probably reflects my caution as an Editor-in-Chief of a medical journal. Medical editors are reluctant to render a public opinion unless they are confident they understand the facts.
MJJC: In your opinion, does Demerol aggravate insomnia as a side effect? Did it play any part in Michael's physical and mental health? What was the best treatment for Michael's insomnia?
Dr. Steve Shafer: There are three questions here. I’ll answer them in order:
Demerol’s chemical name in the United States is “meperidine.” In many countries it is known as “pethidine.” Meperidine has a metabolite, “normeperidine”, that is a nervous system stimulant. As a nervous stimulant, I would expect it to exacerbate insomnia.
The coroner examined both blood and urine for meperidine (Demerol) and normeperidine. Neither could be detected. Thus, meperidine did not play a direct role in Michael Jackson’s death on June 25th. However, you asked a more general question about “play any part in Michael’s physical and mental health.” It is a good question, and I will again need to apologize for not answering it. I have not read Dr. Klein’s medical records or heard a detailed explanation of Michael Jackson’s care. I am uncomfortable speculating without that information.
Sleep disorders are complex, and treating them is a specialized branch of medicine. It is my understanding that any drug that affects the level of consciousness can exacerbate sleep disorders. There is a nice description of sleep disorders, and the treatment of common sleep disorders, at http://www.sleepfoundation.org/artic...s-and-insomnia.
Questions about lorazepam, flumazenil, and ephedrine
MJJC: Could the free lorazepam detected in the gastric liquid be explained by the stomach hemorrhage caused by CPR or even by accidental mixing of adjacent blood at the time of autopsy (as it was suggested by the Coroner, Dr. Rogers in the preliminary, though not mentioned again during the trial)?
Dr. Steve Shafer: Maybe. However, free lorazepam would be expected simply because molecules like lorazepam would be expected to cross from the blood into the stomach, just like they cross into all tissues. That is how the lidocaine and propofol got into the stomach. Lorazepam should behave just the same way.
Additionally, the enzyme beta glucuronidase is secreted by the wall of the stomach into the stomach fluid. Beta glucuronidase is the enzyme that would turn lorazepam glucuronide back into lorazepam. So blood could account for it, but most of it is likely the simple diffusion of lorazepam from the blood into the stomach.
MJJC: Is there any other reason for Flumazenil to be administered apart from reversing the effects of benzodiazepines (in this case Lorazepam)?
Dr. Steve Shafer: No.
MJJC: Does it even make sense to give a person Flumazenil who according to Dr. Murray only received 4 mg of Lorazepam to begin with?
Dr. Steve Shafer: The most critical part of any resuscitation is to move air in and out of the patient’s lungs. The problem with giving flumazenil is that it distracted Conrad Murray from the critical task of moving air in and out of Michael Jackson’s lungs. If there were several people were involved in the resuscitation, then giving flumazenil would have made sense. However, since Conrad Murray was alone, any interruption longer than a few seconds was too long.
MJJC: Can you explain your consideration of the Lorazepam levels, in more detail?
Dr. Steve Shafer: I’ll answer as well as I can, but I’m not sure exactly what you want to know. The lorazepam levels were high enough that you or I would have been very sleepy from them. However, patents become tolerant to lorazepam and related drugs (the “benzodiazepines”). Since Michael Jackson had a fairly high concentration, and according to Conrad Murray that was not enough drug to induce sleep, he must have been tolerant.
The defense wanted to attribute Michael Jackson’s death, in part, to oral lorazepam. The problem with this theory is that there was only a minute amount of lorazepam in Michael Jackson’s stomach. To explain this minute amount, the defense alleged that Michael Jackson swallowed lorazepam about 5 hours before the time of death. If that were true, then the lorazepam concentration would have peaked about the time Conrad Murray claims Michael Jackson was pleading for more drug to fall asleep. So that argument doesn’t make sense.
MJJC: According to autopsy report there was ephedrine found in Michael's body. It's a drug that aggravates insomnia. How ephedrine goes with benzos and propofol, could it subdue effect of these drugs?
Dr. Steve Shafer: There was a bottle of capsules composed of ephedrine, caffeine, and aspirin in the room. Ephedrine is sometimes used in resuscitation. Since there was ephedrine in Michael Jackson’s autopsy urine, as well as the urine that was found at the scene, I would assume that the ephedrine was from oral ingestion, and not from administration as part of the resuscitation.
Ephedrine can reduce the effects of propofol and benzodiazepines on blood pressure and heart rate. Chronic ephedrine might aggravate insomnia.
Question about medical research in general
MJJC: Judge Pastor referred to Murray as making Michael Jackson part of a “scientific experiment”. This could unfortunately dissuade patients from feeling comfortable participating in clinical trials and other types of beneficial scientific and medical research. Can you discuss the important intersection between the research of scientists and the clinical practice of physicians?
Dr. Steve Shafer: I’ve performed dozens of clinical trials. I don’t think this will adversely affect recruiting patients into clinical trials, because this “experiment” bears no resemblance to a scientific study. I think “experiment” is an accurate term, because it correctly implies that Conrad Murray had no idea what he would find day after day of propofol administration. So this was an experiment that he was conducting every day to see how Michael Jackson would respond. However, I don’t think anybody would confuse this experiment with a proper scientific experiment.
The larger question you ask is about the intersection between research and practice. This is an important question, and (fortunately) one that has been given very careful consideration. The answer goes back to the Nuremberg Code, which followed the trial of Nazi doctors guilty of atrocities at the end of World War II. You can find an excellent account on Wikipedia. This was updated by the Belmont Report, published in 1978. Again, there is an excellent account in Wikipedia. As explained in the Belmont Report, “research” differs from clinical practice in that research is a systemic investigation intended to create generalizable knowledge. “Systematic” means that the investigator intentionally gathers data to answer a question. Generalizable knowledge means that the investigator believes the information gathered is useful to others, and intends to “generalize” the knowledge, usually by publishing it. If you Google “Anesthesia & Analgesia policy in institutional review board approval and informed consent for research” you will find an editorial I wrote in March on the subject.
Questions about insomnia
MJJC: Decades of lies, slander, deceit, inhuman treatment from the media and public misconceptions had caused Michael immense hurt, pain and anguish resulting in insomnia. We know Propofol was not the answer, but what do you think he should have done (medically) to treat it?
Dr. Steve Shafer: He should have been in the care of a sleep medicine doctor. He had a terrible affliction, one that requires expert care.
MJJC: Do you think meditation that Murray was talking about in his police interview could really help Michael to sleep?
Dr. Steve Shafer: Maybe. Conrad Murray mentioned both propofol and lorazepam. These are both sedatives that act on the same receptor in the body, the “GABA” receptor. Most sleeping medications also act on GABA, the exceptions being antihistamines (e.g., benedryl) and melatonin. So I would expect these drugs to induce sleep. However, they should not be used to maintain sleep, because the drugs interfere with some of the brain function that is required for sleep to be “restorative”, meaning that it refreshes the brain.
MJJC: Anything you want to say to the members of MJJCommunity and Michael Jackson fans in general.
Dr. Steve Shafer: Once your questions about Michael Jackson’s tragic death have been answered, I encourage you to set it aside. Conrad Murray has been convicted. We have a reasonable understanding of what happened. It’s time to return to the bonds that brought the MJJCommunity together in the first place: your celebration of Michael Jackson’s life, his message, and his music.
I appreciate the opportunity to address your questions, and hope that the answers are helpful to the MJJCommunity.